Socio-economic pressures and customer needs render night work imperative in many occupations. Sleep deprivation, common in night workers, is a major cause of accidents and fatalities. Alertness and sleep are normally rhythmic events synchronized to the light and dark phases of the 24h solar cycle. Rotating or permanent night work cause dissociation of rhythms from the 24h light/dark phases with resultant poor sleep, diminished alertness and mood disturbances. Melatonin is effective in accelerating adjustment to alterations in the 24 h light/dark cycle in certain conditions, e.g., jet lag and blindness. The proposed project tested the hypothesis that melatonin accelerates the adjustment of workers to a reversal in the activity/sleep cycle from daytime to night work by synchronizing sleep to the desired schedule and consequently improving alertness and mood during the waking hours. The hypothesis was tested in an actual work place, a hospital. Subjects were residents, i.e., physicians in training, whose work requires intense alertness and vigilance. The design included two treatment phases for each subject, melatonin and placebo, and two respective baseline phases, one for each treatment; each phase lasts two weeks. The treatment phases consisted of the night float rotation characterized by a sequence of 5-15 days of night work without any daytime duties, thereby involving an abrupt reversal of the wake-sleep schedule. During this work period the residents got 3 days off over 2 weekends. Residents were instructed to take the drug 30 minutes before their desired bedtime, but they omitted taking the drug if bedtime occurred after 1300h. Melatonin or placebo was be administered daily in the morning of the workdays during the night float rotation. On the days off, residents had the option of omitting the drug or taking it at the desired bedtime, which was usually in the evening. Outcome measures included: (1) sleep characteristics obtained by diary and wrist actigraphy; (2) attention assessed by the Conner's continuous performance test (Conners 1995); and (3) mood assessed by the Profile of Mood States (McNair, Lorr et al. 1992). Forty five subjects participated: 28 completed both treatment phases and 17 completed one treatment phase of whom 10 took placebo and 7, melatonin. First, we examined the impact of the night float rotation on sleep, mood and attention of the 38 residents who took placebo, by comparing the outcome measures during the night float rotation with the respective daytime control measures. Residents completed sleep diaries daily and the tests of mood and attention 3 times a week during the two-week night float rotation and during equivalent blocks of time of their daytime rotations. We showed that, despite having ample opportunity to sleep during the day while on night float rotation, residents slept less during the night float rotation than during the nights of their usual daytime rotations, 6.3h +/- 2.5h and 7.2h +/- 1.7h, respectively, p < 0.0001. Also, during night float compared to daytime rotations residents had increased fatigue-inertia scores, 8.7+/- 4.1 and 4.8 +/-2.4, respectively, p < 0.0001, and decreased vigor-activity scores 10.7 +/- 5.4 and 14.8 +/- 5.3, respectively, p = 0.02; The scores for attention were not significantly different between night float and daytime rotations. The correlation coefficients of fatigue with measures of attention were not statistically significant for daytime rotations. However, for night float fatigue correlated with omission errors, r = 0.51, P = 0.001 and with attentiveness r = -0.36, P = 0.03. We concluded that the night float rotation caused deleterious effects on sleep, mood and attention as had been observed in other modalities of shift work. The proposed model of shift work and the outcome measures are not job-specific, hence, the results of the study can be generalized to other occupations which require high level of vigilance and alertness. Next, we examined the effect of melatonin treatment on sleep, mood and attention in the 45 residents. There was no significant difference between melatonin and placebo treatment in measures of sleep, mood and attention of all 45 participants. In the 28 residents who each participated in both treatment conditions, melatonin and placebo, there were two distinct responses of sleep duration to melatonin: it increased by 0.89h +/- 0.62h in 15 residents (responders) and decreased by 0.68h +/- 0.55h in 13 (nonresponders); also, there was a marginal beneficial effect of melatonin on vigor, F (1,26)=4, p=0.056. Side effects were not statistically more frequent on melatonin than on placebo and they were not unusual other than nightmares in one resident taking melatonin. We propose the following explanations for the finding of responders and nonresponders: pharmacogenetic characteristics, individual tolerance to shift work, and a relationship of response to melatonin with tolerance to shift work. Further studies are needed to identify factors that will predict a favorable response to melatonin treatment. The results suggest that melatonin treatment may be beneficial in adaptation to night shift in some workers. The expected benefits of melatonin treatment may lead to development of new strategies for adjustment to night work, resulting in increased safety and reduced accidents and fatalities related to sleep deprivation in night workers.