Studies have shown that some sociodemographic factors, such as marital status, employment status or social class, can affect mental health in different ways for each gender. However, up until now, few research projects have tried to ascertain if the role that reproductive work or psychosocial factors play in mental health is different for men and women. The aim of this study is to assess the differences between men and women in terms of how reproductive work, sociodemographic and psychosocial factors are linked to psychological distress in Spain. A cross-sectional study of 29,478 male and female adults using data gathered for the Spanish National Health Survey 2006 was carried out. Psychological distress was measured using the GHQ-12. The independent variables analyzed were: sociodemographic, psychosocial (family functionality and functional social support) and those related to reproductive work (living with or being in charge of different types of people needing care and number of hours devoted to caregiver tasks). Different independent logistic regression models were developed for men and women. In general, with the exception of men who were more prone to psychological distress if they were signed off work for 3 months or more, no major differences were observed regarding the effect of sociodemographic and psychosocial characteristics on psychological distress. With regard to reproductive work, the likelihood of psychological distress doubles in both sexes when the person lives with someone who needs care. In women, a greater number of hours devoted to caring for another person is associated with an increase in distress. Men play a less frequent role in caregiving, but the impact on psychological distress is similar to that in women. Women experienced more psychological distress when they had to live with or be in charge of a disabled person or different types of persons needing care, while men were not affected by this. Major differences have been identified in terms of psychological distress in women and men in several aspects of reproductive work to date unexplored.