Scholarship has highlighted the importance of kin relations for well-being in adulthood. Much focus has been on relationships between spouses and between parents and children. However, limited research has explored the role of adult sibling relationships in well-being, and no studies have made direct comparisons among the effects of tension with these multiple family members. Using data collected from 495 adult children nested within 254 families, we examined the differential impact of tension with mothers, siblings, and spouses on depressive symptoms in midlife. Separate multi-level regression analyses showed that tension with spouses, mothers, and siblings each predicted depressive symptoms. Combined analyses revealed that greater tension with spouses was associated with higher depressive symptoms, but tension with mothers and siblings was not. However, Wald tests comparing the strength of these associations between tension and depressive symptoms indicated that these associations did not significantly vary across family members. Interactions with gender indicated that tension with mothers was more strongly associated with higher depressive symptoms for women than men. These findings highlight the importance of the quality of relationships with family members on individuals’ psychological well-being, and call for researchers to consider multiple ties and gender when examining family relationships and well-being.