To examine the potential risk factors for work-related fatigue (WRF) among workers in modern industries, the authors analyzed the records of need-for-recovery questionnaires and health checkup results for 1545 employees. Compared with regular daytime workers, and after adjusting for confounders, the workers adapting to day-and-night rotating shift work (RSW) had a 4.0-fold (95% confidence interval [CI] = 2.7-5.9) increased risk for WRF, higher than the 2.2-fold risk (95% CI = 1.5-3.3) for persistent shift workers. Based on highest education level, the male employees with university degrees had the highest adjusted odds ratio (a-OR) 2.8 (95% CI = 1.0-7.8) for complaining of WRF versus compulsory education group. For female workers, currently married/cohabiting status was inversely associated with WRF (a-OR = 0.5; 95% CI = 0.2-0.9), and child-rearing responsibility moderately increased WRF risk (a-OR = 1.9; 95% CI = 1.0-3.7). Day-and-night RSW and the adaptation, educational levels of males, and domestic factors for females contributed to WRF among semiconductor manufacturing employees.