Background: Bipolar disorder is a heritable disorder, and we aimed to assess the impact of family history of mental disorders in first-degree relatives on the severity and course of bipolar disorder. Methods: The Bipolar CHOICE (lithium versus quetiapine) and LiTMUS (optimized treatment with versus without lithium) comparative effectiveness studies were similar trials among bipolar disorder outpatients studying four different randomized treatment arms for 24 weeks. Patients self-reported on six severe mental disorders among first-degree relatives. We performed ANOVA and linear regression regarding disease severity measures, sociodemographic and cardiometabolic markers and mixed effects linear regression to evaluate treatment response. Results: Among 757 patients, 644 (85.1%) reported at least one first-degree relative with a severe mental disorder (mean=2.8; standard deviation=2.2; range=0-13). Depression (67.1%), alcohol abuse (51.0%) and bipolar disorder (47.0%) were the most frequently reported disorders. Familial psychiatric history correlated with several disease severity measures (hospitalizations, suicide attempts, and earlier onset) and sociodemographic markers (lower education and household income) but not with cardiometabolic markers (e.g. cholesterol or waist circumference) or cardiovascular risk scores, e.g. the Framingham risk score. Patients with familial psychiatric history tended to require more psychopharmacological treatment (p=0.054) but responded similarly (all p>0.1) to all four treatment arms. Conclusions: Our findings indicate that familial psychiatric history is common among outpatients with bipolar disorder and correlates with disease severity and sociodemographic measures. Patients with a greater familial psychiatric load required more intense treatment but achieved similar treatment responses compared to patients without familial psychiatric history.