BACKGROUND: Pre-exposure prophylaxis (PrEP) programs have been implemented in multiple countries. Evidence from clinical trials and cohort studies has proven the safety and effectiveness of PrEP. However, minimizing drug-related adverse effects and cost should be primarily considered in PrEP. Most trials used tenofovir combined with emtricitabine as the intervention; yet, the use of tenofovir disoproxil fumarate (TDF) (ie, Tenofovir) alone has not been thoroughly evaluated. Furthermore, the medication regimen in most trials was used every day, with a few studies proposing an optimal medication regimen for PrEP. OBJECTIVE: This study was designed to systematically evaluate the preventive efficacy and safety profile of TDF-based PrEP in the Chinese population. We also aimed to explore medication compliance, changes in sexual behavior, and hazard factors of HIV infection. METHODS: We conducted a pragmatic randomized controlled trial (RCT) to evaluate the effectiveness and safety of TDF for HIV PrEP. Participants were randomly assigned (1:1:1) to a time-driven group (TDF 300 mg administered orally once daily), an event-driven group (TDF 300 mg administered orally 24 to 48 h before sexual activity and 2 hours after sexual activity, not exceeding 300 mg within 24 h), or an untreated control group. The primary outcomes were the effectiveness and safety of TDF during periods of PrEP use. Secondary outcomes focused on the effectiveness of TDF among participants with good compliance during PrEP use. Tertiary outcomes included the risk factors of HIV infection and behavioral changes from PrEP initiation to the last visit. For ethical reasons, all participants received condoms and health education. This study was registered with the Chinese Clinical Trial Registry (ChiCTR-TRC-13003849). RESULTS: A total of 1914 participants underwent randomization. During the follow-up of 3513.5 person-years from June 2013 to May 2016, HIV seroconversion was observed in 30 persons (2.02 per 100 person-years) in the time-driven group (time-driven vs control group: hazard ratio [HR] 0.93, 95% CI 058-1.51; P=.78), 35 (1.73 per 100 person-years) in the event-driven group (event-driven group vs control group: HR 0.83, 95% CI 0.52-1.31; P=.42), and 37 (2.06 per 100 person-years) in the control group. Post hoc analysis showed that participants with good medication compliance reduced their HIV infection risk by 53% (P=.01) and event-driven medication with good compliance reduced the risk by 62% (P=.009). We recorded no severe adverse events during the trial. For tertiary outcomes, low medication compliance, sexual role, no condom use, and more number of sexual partners remained significantly associated with HIV risk. CONCLUSIONS: The TDF-based PrEP is ineffective without good adherence. However, when medication compliance is achieved, event-driven dosing is recommended as an optimal PrEP regimen.