The double-blind phase of the randomized ANRS IPERGAY trial, evaluating sexual activity-based oral HIV pre-exposure prophylaxis (PrEP), was conducted among high-risk men who have sex with men (MSM). Results showed an 86% (95% CI: 40–98) relative reduction in HIV incidence among participants with tenofovir disoproxil fumarate–emtricitabine vs. placebo. The present pooled analysis aimed to analyze (i) participants’ adherence to the prescribed treatment and/or condom use during sexual intercourse and (ii) sexual behavior during the double-blind phase of the study. Four hundred MSM were enrolled in the trial. Every 2 months they completed online questionnaires collecting sexual behavior and PrEP adherence data regarding their most recent sexual intercourse. A total of 2232 questionnaires (M0–M24) were analyzed. Changes over time were evaluated using a mixed model accounting for multiple measures. Irrespective of sexual partner and practice type, on average, 42.6% (min: 32.1–max: 45.8%) reported PrEP use only during their most recent episode of sexual intercourse; 29% (22.9–35.6%) reported both PrEP and condom use; 11.7% (7.2–18.9%) reported condom-use only, and 16.7% (10.8–29.6%) reported no PrEP or condom use with no significant change during the study. Scheduled (i.e., correct) PrEP use was reported on average by 59.0% (47.2–68.5%) of those reporting PrEP use during their most recent sexual intercourse. Overall, 70.3% (65.3–79.4%) and 69.3% (58.3–75.4%) of participants reported, respectively, condomless anal and condomless receptive anal intercourse during their most recent sexual encounter without significant change during followup. Overall, on average 83.3% (min: 70.4–max: 89.2%) of participants protected themselves by PrEP intake or condom use or both during the trial, and no increase in at-risk sexual practices was observed. None of these indicators showed significant trend during the follow-up, although we found a tendency toward decrease (p = .19) of the median number of sexual partners strengthening the absence of behavioral disinhibition. On-demand PrEP within a comprehensive HIV prevention package could improve prevention in MSM.