Abstract Objective. To evaluate the efficacy of a single prophylactic dose of actinomycin D (Act-D) in the reduction of postmolar gestational trophoblastic neoplasia (GTN) in adolescents with high-risk hydatidiform mole (Hr-HM). Methods. In a retrospective study, 60 adolescents with Hr-HM were selected from a cohort of patients with gestational trophoblastic disease (GTD) followed at Santa Casa, Porto Alegre, Brasil. Twenty-nine received a single dose of Act-D at the time of uterine evacuation as prophylactic chemotherapy (P-chem) (study group) and 31 patients with the same risk factors did not received P-chem (control group). Patient follow-up was the same in both groups. Each group was analyzed for number of adolescents with postmolar GTN, morbidity associated with postmolar GTN, and reproductive outcomes. Results. Postmolar GTN was diagnosed in two (6.9%) adolescents (95% CI, 0.0–16.1) in the study group and in 9 (29.0%) patients (95% CI, 13–45) in the control group. The reduction of postmolar GTN with a single dose of Act-D used as P-chem was 76% (relative risk = 0.24; 95% CI, 0.06–0.99). Adverse effects of P-chem were minor. In the follow-up, when postmolar GTN were diagnosed, severity of disease was not increased, compliance with follow-up was not reduced, and reproductive outcomes after discharge were similar. Conclusions. P-chem with a single dose of Act-D reduced postmolar GTN in 76% during follow-up of adolescents with Hr-HM. Since this regimen may reduce treatment costs, without affecting compliance with follow-up, it can be adopted by any Trophoblastic Disease Center.