Since many countries in sub-Saharan Africa are willing to implement HIV oral pre-exposure prophylaxis (PrEP) for men who have sex with men (MSM), data are needed to assess its feasibility and relevance in real life. The study objectives were to assess drug uptake, adherence, condom use and number of sexual partners, HIV incidence and trends in the prevalence of gonorrhoea and chlamydia. In this oral PrEP demonstration study conducted prospectively in Benin, a combination of tenofovir disoproxil fumarate-TDF 300 mg and emtricitabine-FTC 200 mg (TDF-FTC) was offered daily or on-demand to MSM. Participants were recruited from 24 August to 24 November 2020 and followed over 12 months. At enrolment, month-6 and month-12, participants answered to a face-to-face questionnaire, underwent a physical examination and provided blood samples for HIV, gonorrhoea and chlamydia. Overall, 204 HIV-negative men initiated PrEP. The majority of them (80%) started with daily PrEP. Retention rates at month-3, 6, 9 and 12 were 96%, 88%, 86% and 85%, respectively. At month-6 and month-12, respectively, 49% and 51% of the men on daily PrEP achieved perfect adherence (self-reported), that is seven pills taken during the last week. For event-driven PrEP, the corresponding proportions for perfect adherence (last seven at-risk sexual episodes covered) were 81% and 80%, respectively. The mean number (standard deviation) of male sexual partners over the last 6 months was 2.1 (1.70) at baseline and 1.5 (1.27) at month-12 (p-value for trend <0.001). Consistent condom use during the last 6 months was 34% (enrolment), 37% (month-6) and 36% (month-12). Three HIV seroconversions (2-daily and 1-event-driven) were recorded. Crude HIV incidence (95% confidence interval) was 1.53 (0.31-4.50)/100 person-years. Neisseria gonorrhoeae and/or Chlamydia trachomatis prevalence at the anal and/or pharyngeal and/or urethral sites was 28% at baseline and 18% at month-12 (p-value = 0.017). In West Africa, oral PrEP introduction in routine practice as a component of a holistic HIV prevention package is feasible and may not result in a significant increase in condomless sex among MSM. Since HIV incidence was still higher, additional interventions, such as culturally tailored adherence counselling, may be needed to optimize the benefits of PrEP.