We examined how work-family conflict (WFC) mediated the relationship between social support (supervisor and family) and burnout, and how sex moderated this relationship (N = 343 Spanish workers). The results sustained hypotheses in accordance with a biosocial model of sex differences. There were full mediation effects of work interference with family (WIF) in the association of work support with burnout for men, and of family support with burnout for women. This suggests that sex moderated these mediation processes. The findings are discussed in terms of a shift in the differential assignment of family roles to men and women, despite the fact that women might be the main contributors to domestic work and related tasks.