Burnout is highly prevalent in medical residents. In order to prevent or reduce burnout in medical residents, we should gain a better understanding of contributing and protective factors of burnout. Therefore we examined the associations of job demands and resources, home demands and resources, and work-home interferences with burnout in male and female medical residents. This study was conducted on a nation-wide sample of medical residents. In 2005, all Dutch medical residents (n = 5245) received a self-report questionnaire on burnout, job and home demands and resources and work-home interference. Path analysis was used to examine the associations between job and home characteristics and work-home interference and burnout in both males and females. In total, 2115 (41.1%) residents completed the questionnaire. In both sexes emotional demands at work and the interference between work and home were important contributors to burnout, especially when work interferes with home life. Opportunities for job development appeared to be an important protective factor. Other contributing and protective factors were different for male and female residents. In females, social support from family or partner seemed protective against burnout. In males, social support from colleagues and participation in decision-making at work seemed important. Effectively handling emotional demands at work, dealing with the interference between work and home, and having opportunities for job development are the most essential factors which should be addressed. However it is important to take gender differences into consideration when implementing preventive or therapeutic interventions for burnout in medical residents.