Adolescent study participants who engaged in a brief, family-centered intervention (the Family Check-Up, FCU) were later assessed for the intervention's effects on high-risk sexual behavior (HRSB) in early adulthood (age 22). Participants (N = 998 adolescents and their families) were randomly assigned to a family-centered intervention in sixth grade and were offered a gated, multilevel intervention that included (a) a school-based family resource center, (b) the FCU, and (c) more intensive, family-based treatment. All services were voluntary, but high-risk families were actively recruited into the FCU. Approximately 23% of the intervention families engaged in the FCU and approximately 18% engaged in more intensive treatment. Using an intent-to-treat design, we found that the direct effect of the FCU on HRSB was not significant; however, an analysis of the developmental processes indicated that intervention families demonstrated improved family relationship quality when compared to control families, which in turn resulted in lower levels of HRSB in early adulthood. Furthermore, the significant effect of family relationship quality on HRSB was mediated by differences in parental monitoring and early sexual activity, and these effects varied as a function of gender and ethnicity. Indirect effects of the FCU on HRSB were significant via multiple different pathways. The implications of these findings for enhancing the impact of family-centered interventions are discussed.