Background Several observational studies have reported that HIV-1 acquisition seems to be higher in women who use depot medroxyprogesterone acetate (DMPA) than in those who do not use hormonal contraception. We aimed to assess whether two injectable progestin-only contraceptives, DMPA and norethisterone enanthate (NET-EN), confer diff erent risks of HIV-1 acquisition. Methods We included data from South African women who used injectable contraception while participating in the VOICE study, a multisite, randomised, placebo-controlled trial that investigated the safety and effi cacy of three formulations of tenofovir for prevention of HIV-1 infection in women between Sept 9, 2009, and Aug 13, 2012. Women were assessed monthly for contraceptive use and incident infection. We estimated the diff erence in incident HIV-1 infection between DMPA and NET-EN users by Cox proportional hazards regression analyses in this prospective cohort. The VOICE trial is registered with ClinicalTrials.gov, NCT00705679. Findings 3141 South African women using injectable contraception were included in the present analysis: 1788 (56 9%) solely used DMPA, 1097 (34 9%) solely used NET-EN, and 256 (8 2%) used both injectable types at diff erent times during follow-up. During 2733 7 person-years of follow-up, 207 incident HIV-1 infections occurred (incidence 7 57 per 100 person-years, 95% CI 6 61-8 68). Risk of HIV-1 acquisition was higher among DMPA users (incidence 8 62 per 100 person-years, 95% CI 7 35-10 11) than among NET-EN users (5 67 per 100 person-years, 4 35-7 38; hazard ratio 1 53, 95% CI 1 12-2 08; p=0 007). This association persisted when adjusted for potential confounding variables (adjusted hazard ratio [aHR] 1 41, 95% CI 1 06-1 89; p=0 02). Among women seropositive for herpes simplex virus type 2 (HSV-2) at enrolment, the aHR was 2 02 (95% CI 1 26-3 24) compared with 1 09 (0 78-1 52) for HSV-2-seronegative women (Pinteraction=0 07). Interpretation Although moderate associations in observational analyses should be interpreted with caution, these fi ndings suggest that NET-EN might be an alternative injectable drug with a lower HIV risk than DMPA in high HIV-1 incidence settings where NET-EN is available.