Exhaustion is consistently found to be more prevalent in women than in men. Women suffer from job strain more often, which may constitute a partial explanation for this phenomenon, but experienced shortcomings in combining work and family demands may also contribute to ill health. The aim of this study was to investigate, and analyse by gender, how work-related and family-related factors, as well as the interface between them, i.e. work-to-family conflict (WFC) and family-to-work conflict (FWC), are related to exhaustion. The study was crosssectional with self-administered questionnaires assessing exposures and outcome with previously well validated instruments. The participants were 2,726 men and 2,735 women, aged 45 to 64, vocationally active, and residing in Malmö, Sweden. Sixteen percent of the women and 8% of the men considered themselves exhausted. WFC, FWC, job strain, and low job support were all strongly correlated to exhaustion in both genders. In the multivariate analyses, adjusting for other work and family risk factors, WFC and FWC remained statistically significant risk factors for exhaustion in both men and women. Job strain, low job support, and having a somatic disorder were also independently associated with exhaustion. While WFC was more prevalent among men, it was more strongly associated with exhaustion in women than in men. In women, WFC and FWC contributed to a larger part of the explanatory power of the model, which amounted to 22% of the variance in women and 14% in men. The results imply that the concept of 'work stress' should be regarded in a wider context in order to understand gender related issues of exhaustion among vocationally active individuals.