Objectives: The aim of the current study was to elucidate prospective effects of both shift schedules and work environment on mental distress. Methods: A total of 2059 nurses participated at baseline (38.1%), and 1582 nurses completed wave 2 of the survey (76.8%). Psychosocial work factors were measured by the General Nordic Questionnaire for Psychological and Social factors at work and the Swedish Demand–Control–Support Questionnaire. Mental distress was measured by Hospital Anxiety and Depression Scale. Results: Shiftwork was not associated with ‘‘caseness’’ anxiety or depression. Effects of shiftwork on mental distress were not moderated by psychosocial work factors. Mental distress predicted role clarity, role conflict, fair leadership, and social support. Job demands predicted symptoms of depression. Conclusions: Whether psychosocial working conditions buffer mental health effects of shiftwork remains undecided. Prospective studies with multiple measurement points are needed to elucidate potential mutual relationships between work factors and mental distress.