Objective: Two-generation studies demonstrate that treating maternal depression benefits school-age children. Although mothers prefer psychotherapy to medication, little is known about how psychotherapy for maternal depression affects offspring, especially in very high-risk families in which both mothers and children concurrently meet syndromal criteria for psychiatric disorders. This trial evaluated the effects of 2 brief psychotherapies for maternal depression on very high-risk families. Method: Mothers with major depressive disorder were randomly assigned to 9 sessions of either brief interpersonal psychotherapy for mothers (IPT-MOMS; n = 85) or brief supportive psychotherapy (BSP; n = 83). Independent assessors evaluated mothers and their children, ages 7 to 18 years, diagnosed with at least 1 internalizing disorder, every 3 months over the course of 1 year. Results: Symptoms and functioning of mothers and children improved significantly over time, with no between-group differences. However, children of mothers assigned to BSP had more outpatient mental health visits and were more likely to receive antidepressant medication. Mothers reported greater satisfaction with IPT-MOMS than BSP. Improvement in mothers’ depressive symptoms was associated with improvement in child functioning in time-lagged fashion, with children improving 3 to 6 months after mothers improved. Antidepressant medication use and number of mental health visits received by children did not affect outcomes. Conclusion: IPT-MOMS and BSP demonstrated comparable beneficial effects on maternal depression. Children’s functioning improved following maternal improvement, independent of youths’ treatment. Children of mothers randomized to IPT-MOMS, compared with BSP, achieved comparable outcomes despite less follow-up treatment. Observation of lagged association between maternal improvement and change in child functioning should influence treatment planning for families.