Objectives To investigate whether work-time influence moderated the effect of shift work on psychological well-being measured as vitality, mental health, somatic stress symptoms, and disturbed sleep. Methods We used questionnaire data from 2,148 health care workers who finished their education in 2004 and were followed during their first 2 years of employment in the eldercare and health care sectors. We analyzed the effect of shift work, work-time influence, and the combination of these two variables adjusted for differences in baseline psychological well-being, background factors, and psychosocial work environment. Results Surprisingly, in this cohort, shift workers had higher vitality and better mental health than day workers. The combination of shift work and moderate or low work-time influence was associated with lower vitality, worse mental health, and more somatic stress symptoms than would have been expected when adding the separate effects of working hours and work-time influence. Work-time influence did not have any effect among day workers. Conclusion Shift workers appear to be especially vulnerable to the negative effect of moderate or low work-time influence.