Objective: To investigate the effects of sleep deprivation on physical health, cognition, and work performance in residents and interns who suffer from chronic sleep deprivation. Methods: Fifty-eight residents and interns were recruited in this study. They completed sleep diary for 2 weeks and questionnaires including health complaints, daytime sleepiness and work performance, and were evaluated with actigraphy. Stroop test, continuous performance test (CPT), trail-making test (TMT) and Korean-California verbal learning test (K-CVLT) were done as neuropsychological evaluations. Subjects were divided into severe sleep deprived (S-SD, average night sleep less than 4 h), mild to moderate deprived (M-SD, 4–6 h), and non-sleep deprived (Non-SD, more than 6 h) groups. Results: Forty-one subjects (70.7%) were sleep-deprived. Mean sleep duration was 5.0 ± 1.2 h/night and work duration was 14.9 ± 2.7 h/day. The S-SD group showed higher Epworth Sleepiness Scales than M-SD and Non-SD groups. Severe sleep deprivation was associated with higher level of stress, more frequent attention deficit, and difficulty in learning (P < 0.05), but not with decreased neuropsychological test results. Conclusion: These results suggested that sleep deprivation in residents and interns might affect their health as well as work performance that might influence the quality of patient care, although active compensatory brain mechanisms could be involved to preserve their performance.