Health-related quality of life (HRQL) is an important measure of health outcome in working and healthy populations. Here, we investigated the impact of effort-reward imbalance (ERI), a representative work-stress model, on HRQL of Japanese working men. The study targeted 1,096 employees from a manufacturing plant in Japan. To assess HRQL and ERI, participants were surveyed using the Japanese version of the Short-Form 8 Health Survey (SF-8) and effort-reward imbalance model. Of the 1,096 employees, 1,057 provided valid responses to the questionnaire. For physical summary scores, the adjusted effort-reward imbalance odds ratios of middle vs. bottom and top vs. bottom tertiles were 0.24 (95% confidence interval, 0.08-0.70) and 0.09 (95% confidence interval, 0.03-0.28), respectively. For mental summary scores, ratios were 0.21 (95% confidence interval, 0.07-0.63) and 0.07 (95% confidence interval, 0.02-0.25), respectively. These findings demonstrate that effort-reward imbalance is independently associated with HRQL among Japanese employees.