Pre-exposure prophylaxis is effective in preventing HIV, but data show that its effectiveness is compromised by suboptimal adherence. This randomized controlled trial (n = 69) tested the impact of an iPhone game, Viral Combat, on PrEP adherence over 24 weeks. Tenofovir-diphosphate in red blood cells was collected as a biological outcome of adherence. At 24-weeks, intervention participants were 3.75 (95% CI: 1.20-11.77; p = 0.02) times as likely to engage in optimal PrEP dosing compared to controls. Viral Combat showed preliminary efficacy in improving PrEP adherence for diverse young men who have sex with men.