The relationship between physical and mental fatigue is not well understood or well documented, a lapse that affects understanding of the interaction between loading and unloading activities and safe operation in the trucking industry. This experiment addresses the effects of loading and unloading on driving performance by measuring driving impairment in volunteer truck drivers operating a truck-driving simulator. Ten drivers participated, each for 17 days, including 2 driving weeks of 5 days with 14-h duty cycles separated by two 58-h rest periods. During one of the driving weeks, participants were given a significant hand-loading task, 3 hours of hand-loading pallets of boxes on 3 of 5 days; during the remaining week, only driving tasks were scheduled. Performance measurement focused on driver responses to planned and unplanned crash-likely challenges and vigilance tasks, supported by simulator-mediated driving indicators, such as lane-keeping performance. Measures of subjective drowsiness also were maintained. The effects of the loading and unloading task were mixed. There was an initial improvement in alertness, apparently because of the break in activity and a period of exercise; however, this effect wore off as the day progressed and may have contributed to a decrease in overall performance after 12 to 14 h of duty.