South Africa has a large burden of bacterial sexually transmitted infections (STIs) with high rates among men who have sex with men (MSM). Randomised controlled trials have recently demonstrated high effectiveness of doxycycline post-exposure prophylaxis (PEP) for prevention of bacterial STIs in MSM, with 70% - 85% reductions in infection and syphilis, and approximately 50% reduction in infection. Doxycycline PEP was not demonstrated to be effective in reducing and infection among Kenyan cisgender women. Although no worrisome trends in antimicrobial resistance (AMR) were observed in the trials, important concerns remain about doxycycline PEP and AMR development in STIs, other pathogens, commensals, and the microbiome. Tetracycline resistance in is already widespread in South Africa, but emergence of AMR in other STIs would be concerning. Larger sample sizes of doxycycline PEP users with longer follow-up time are needed to understand the impact that doxycycline PEP may have on AMR at individual and population level. In this opinion article, we weigh the benefits of doxycycline PEP for prevention of bacterial STIs against the existing AMR concerns and data gaps in the South African context. Based on the current evidence, we conclude that it would be reasonable to offer doxycycline PEP to high-risk MSM on a case-by-case basis, provided that it is offered by experienced sexual health clinicians in settings that have access to diagnostic STI testing and ongoing AMR surveillance.