BACKGROUND: Over the last decade, syphilis epidemics have resurged around the world, particularly among gay men. An innovative public health response could be the use of chemoprophylaxis. We sought out to determine the acceptability of syphilis chemoprophylaxis and its likely population effectiveness if it were adopted. METHODS: We conducted a mixed-methods study. An online survey (n = 2095 participants) and focus groups (n = 23 participants) were conducted to determine whether syphilis chemoprophylaxis is likely to be acceptable to gay men in Australia. We also developed an individual-based mathematical model that simulated a population of gay men, to explore the potential impact of introducing chemoprophylaxis. RESULTS: Of the 2095 gay men surveyed, 52.7% (95% confidence interval, 50.6%-54.8%) indicated that they would be very likely or slightly likely to use chemoprophylaxis to reduce their chance of acquiring syphilis, increasing to 75.8% (95% confidence interval, 74.0%-77.6%) if chemoprophylaxis would help reduce infections in the gay community. In this model, 70% use-effectiveness of chemoprophylaxis used by 50% of gay men is expected to reduce the number of syphilis cases by ∼50% after 12 months and 85% after 10 years. The majority of the prevention efforts can be gained by targeting subpopulations of men with higher sexual activity. CONCLUSIONS: Chemoprophylaxis offers promise as an acceptable and effective intervention for mitigating syphilis epidemics. The outcomes of a planned placebo-controlled syphilis chemoprophylaxis trial are eagerly anticipated.