Background Absence due to mental disease in the workplace has become a global public health problem. We aimed to evaluate the influence of presenteeism on depression and absence due to mental disease. Methods A prospective study of 1831 Japanese employees from all areas of Japan was conducted. Presenteeism and depression were measured by the validated Japanese version of the World Health Organization Health and Work Performance Questionnaire (WHO-HPQ) and the K6 scale, respectively. Absence due to mental disease across a 2-year follow up was surveyed through medical certificates obtained for work absence. Results After adjusting for age and gender, participants with higher rates of sickness absolute and relative presenteeism (the lowest tertile of the scores) were significantly more likely to be absent due to mental disease (OR=4.40, 95% CI: 1.65-11.73, and OR=3.31, 95% CI: 1.50-7.27). Subsequently, higher rates of sickness absolute or relative presenteeism were significantly associated with higher rates of depression (K6=13) one year later (OR=3.79, 95% CI: 2.48-5.81, and OR=2.89, 95% CI: 1.98-4.22). Limitations The number of females in the sample was relatively small. However, the rates of absence for females with and without mental illness did not significantly differ from those of men. Conclusions More sickness presenteeism scores were found to be related to higher rates of depression and absence due to mental disease in this large-scale cohort of Japanese workers. Measurement of presenteeism could be used to evaluate the risk for depression and absenteeism. Furthermore, our findings suggest that intervention to improve presenteeism would be effective in preventing depression and absence due to mental illness.