BACKGROUND: Mood disorders, including depressive and bipolar disorders, begin in late adolescence to early adulthood, tend to run in families, and present early with subthreshold symptoms. They have been associated with differential connectivity in 3 core networks: the default mode network (DMN), cognitive executive network (CEN), and salience network (SN), but it remains unclear whether differences in connectivity in the DMN, CEN, and SN are associated with familial risk for mood disorders. METHODS: We recruited youth aged 9-19 years, including offspring of parents with major depressive or bipolar disorders (familial high risk [FHR]) and offspring of parents with no mood disorder (controls) for a resting-state functional magnetic resonance imaging study. We tested associations between family history of major mood disorders and connectivity within and between the DMN, CEN, and SN. RESULTS: We included 215 youth: 126 at FHR with a mean age of 13.38 (standard deviation [SD] 2.91) years and 79 controls with a mean age of 13.17 (SD 2.67) years. Mean connectivity in the DMN (β = 0.003, 95% confidence interval [CI] -0.023 to 0.029), CEN (β = -0.009, 95% CI, -0.070 to 0.089), and SN (β = -0.010, 95% CI -0.071 to 0.051) in the FHR group was similar to that of controls. Moreover, DMN, CEN, and SN connectivity was not significantly associated with depressive symptoms. LIMITATIONS: Given that brain connectivity changes over the developmental period, longitudinal studies would improve understanding of how this change occurs in familial risk groups to identify critical time periods for intervention or prevention of mood disorders. CONCLUSION: Connectivity within and between the DMN, CEN, and SN is not a neural indicator of familial risk for major mood disorders.