Little research has tested HIV/sexually transmitted infection (STI) risk-reduction interventions’ effects on early adolescents as they age into middle and late adolescence. This study tested whether intervention-induced reductions in unprotected intercourse during a 12-month period endured over a 54-month period and whether the intervention reduced the prevalence of STIs, which increase risk for HIV. Grade 6 learners (mean age= 12.4 years) participated in a 12-month trial in Eastern Cape Province, South Africa, in which 9 matched pairs of schools were randomly selected and within pairs randomized to a theory-based HIV/STI risk-reduction intervention or an attention-control intervention. They completed 42-and 54-month postintervention measures of unprotected intercourse (the primary outcome), other sexual behaviors, theoretical constructs, and, at 42-and 54-month follow-up only, biologically confirmed curable STIs (chlamydial infection, gonorrhea, and trichomoniasis) and herpes simplex virus 2. The HIV/STI risk-reduction intervention reduced unprotected intercourse averaged over the entire follow-up period (OR= 0.42, 95% CI [0.22, 0.84]), an effect not significantly reduced at 42-and 54-month follow-up compared with 3-, 6-, and 12-month follow-ups. The intervention caused positive changes on theoretical constructs averaged over the 5 follow-ups, although most effects weakened at long-term follow-up. Although the intervention’s main effect on STIs was nonsignificant, an Intervention Condition× Time interaction revealed that it significantly reduced curable STIs at 42-month follow-up in adolescents who reported sexual experience. These results suggest that theory-based behavioral interventions with early adolescents can have long-lived effects in the context of a generalized severe HIV epidemic.(PsycINFO Database Record (c) 2017 APA, all rights reserved)