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This phase 3, double-blind, randomised trial across North and South America, Thailand and South Africa evaluated the safety and efficacy of subcutaneous lenacapavir. 4634 people reporting no HIV test or pre-exposure prophylaxis (PrEP) use in the previous 3 months underwent HIV screening and contributed to the estimation of background HIV incidence; 3271 were HIV-negative (>14% transgender women, 67% Hispanic) and randomised 2:1 to twice-yearly lenacapavir or daily emtricitabine-tenofovir disoproxil fumarate (F/TDF) plus corresponding matched placebo, and 423 tested HIV-positive, were referred to care and their trial participation ended. Background HIV incidence in the screened population was 2.37/100 person-years (95% CI 1.65 to 3.42). The incidence of HIV in the lenacapavir group was 96% lower than background incidence (incidence rate ratio (IRR)=0.04,0.01–0.18) and was 89% lower than that with F/TDF (IRR=0.11, 0.02–0.51). Among 2179 participants in the lenacapavir group, 2 acquired HIV and had resistance mutations; 9 F/TDF infections resulted from low/non-adherence or discontinuation (1 had a resistance mutation). Incidence of serious adverse events was similar between groups. Twice-yearly lenacapavir is efficacious and may enhance uptake in this population.