A novel approach to identify at-risk periods among orthopedic surgical residents may direct fatigue risk mitigation and facilitate targeted interventions. A prospective cohort study with a minimum 2-week continuous assessment period. Data on sleep and awake periods were processed using the sleep, activity, fatigue, and task effectiveness model. Rotations at 2 academic tertiary care centers. Twenty-seven of 33 volunteer orthopedic surgical residents (82%) completed the study, representing 65% (33 of 51) of the orthopedic residency program. Residents' sleep and awake periods were continuously recorded via actigraphy, and a daily questionnaire was used to analyze mental fatigue. Percentage of time at less than 80% mental effectiveness (correlating with an increased risk of error), percentage of time at less than 70% mental effectiveness (correlating with a blood alcohol level of 0.08%), the mean amount of daily sleep, and the relative risk of medical error compared with chance. Residents were fatigued during 48% and impaired during 27% of their time awake. Among all residents, the mean amount of daily sleep was 5.3 hours. Overall, residents' fatigue levels were predicted to increase the risk of medical error by 22% compared with well-rested historical control subjects. Night-float residents were more impaired (P = .02), with an increased risk of medical error (P = .045). Resident fatigue is prevalent, pervasive, and variable. To guide targeted interventions, fatigue modeling can be conducted in hospitals to identify periods, rotations, and individuals at risk of medical error.