Lesotho is a small, landlocked country in southern Africa with a population of approximately 2 million persons, approximately two thirds of whom live in rural areas (1). Lesotho has the second highest prevalence of HIV infection in the world (2). In 2017, 25.6% of persons aged 15-59 years living in Lesotho were HIV-positive (3). Strategies implemented in recent years to control HIV include efforts to reduce mother-to-child transmission and improve coverage with antiretroviral therapy, as well as increasing testing for HIV. Among persons aged 15-24 years, the HIV prevalence among females in 2017 (11.1%) was approximately three times that among males (3.4%) (3). The Determined, Resilient, Empowered, AIDS-Free, Mentored, and Safe (DREAMS)* program in Lesotho was started during October 2016 in two districts. DREAMS comprises a package of biomedical, behavioral, and structural interventions to address factors that make adolescent girls and young women vulnerable to HIV acquisition (4). The goal of the DREAMS program was to decrease HIV incidence among adolescent girls and young women by 25% after 1 year and by 40% after 2 years (4). After 3.5 years of program implementation in Lesotho, new HIV diagnoses among adolescent girls and young women attending antenatal care (ANC) decreased 71.4% in the two districts that implemented DREAMS compared with a reduction of 48.4% in three comparison districts without the program (p = 0.002). During 2016-2020, reductions in new HIV diagnoses among adolescent girls and young women attending ANC in Lesotho have been substantial, both in districts that have and have not implemented the DREAMS program (DREAMS and non-DREAMS districts). Apart from the DREAMS program, the decrease in new HIV diagnoses might be a result of the reduction in viral load in the population because more persons living with HIV infection became virally suppressed while on antiviral therapy, as well as other interventions such as preexposure prophylaxis, voluntary medical male circumcision, behavior change, and increased HIV diagnostic coverage.