We tested the combined effects of work schedule and task factors on upper-extremity fatigue in the laboratory during 8-h and 12-h shift schedules. Participants performed a simulated manual assembly task at three repetition rates and three torque loads and self-adjusted their work cycle duration to maintain fatigue at moderate levels. Work cycle durations decreased with increases in both load level and repetition rate. Fatigue was observed more quickly with increasing time on shifts and during night shifts compared with day shifts. Work schedule effects were most apparent at lighter workloads, with minimal differences at higher workloads. The highest fatigue levels were observed during 12-h night shifts, with similar levels reached by the end of both the week of 8-h night shifts and the week of 12-h day shifts. Overall durations were 20%-30% shorter than in previous short-term studies, which was likely a result of the more realistic work schedules used in this study. Results from this study could be applied to the design of work-rest schedules for manual tasks involving the upper extremities.