HPTN 084 investigators conducted this study among sexually active adolescent girls in South Africa, Uganda, and Zimbabwe to support potential licensing of long-acting injectable cabotegravir (CAB-LA) for HIV prevention in adolescents. Participants were recruited from the community, reproductive health clinics, and through referral; all weighed at least 35 kg, had no serious health conditions, and were required to use long-acting reversible contraception. After a five-week oral lead-in (step 1), participants transitioned to the injection phase of five doses of CAB-LA (step 2). Before each injection, participants underwent rapid antibody tests and laboratory-based Ag/Ab assays. Fifty-two individuals received all five scheduled doses (29% were obese or overweight, 25% had a male sex partner with known HIV, and 22% engaged in transactional sex): none acquired HIV. Ninety-three percent reported at least one adverse event of grade 2 or higher: the most frequent events were transient asymptomatic laboratory abnormalities, most deemed unrelated to CAB-LA. There were no product-related serious events or associated discontinuations. Injection site reactions were reported by 26%, and typically occurred after the first or second dose. Overall, 62% of participants indicated they would prefer using CAB-LA over other prevention products, and the majority elected to continue/resume CAB-LA in the open-label extension rather than transition to oral TDF/FTC through a national program.