OBJECTIVE: This study examined if associations between body mass index (BMI) and mental and physical health were independent of genetic and familial factors. METHOD: Data from 2831 twins (66% female) were used in an epidemiological co-twin control design with measures of BMI and mental and physical health outcomes. Generalized estimating equation regressions assessed relationships between BMI and health outcomes controlling for interdependency among twins and demographics. Within-pair regression analyses examined the association of BMI with health outcomes controlling for genetic and familial influences. RESULTS: Adjusted analyses with individual twins found associations in women between BMI and perceived stress (P=.01) and depression (P=.002), and the link between BMI and depression (P=.03) was significant in men. All physical health outcomes were significantly related to BMI. Once genetic and familial factors were taken into account, mental health outcomes were no longer significantly associated with BMI. BMI in women remained related to ratings of physical health (P=.01) and body pain (P=.004), independent of genetic and familial influences. CONCLUSION: These findings suggest that genetic and familial factors may account for the relationship between increased weight and poor mental health.