Female sex workers (FSW) are a key population who experience a disproportionately high burden of HIV and sexually transmitted infections (STIs). A growing body of evidence suggests that financial incentives can reduce risky sexual behavior and reduce HIV/STI incidence, however few studies have examined a lottery-based incentive mechanism or been conducted with FSW. We examined the effect of a lottery intervention on combined HIV/HSV2 incidence among FSW. The RESPECT II trial was an unmasked, two-arm, parallel group randomized controlled trial conducted in Dar es Salaam, Tanzania (AEA RCT registry: AEARCTR-0002677). Individuals who were ≥ 18 years of age, HIV-negative, not currently pregnant, exchanged sex for money in the past six months, and living in Dar es Salaam were eligible. Participants were randomized in a 1:1 ratio to the basic test group (control) which included testing and counseling for HIV and biweekly text messages with information on safe sex practices, or to the lottery group, which provided the basic test group intervention plus entry into a weekly lottery with a 100,000 TZS (~ $50 USD) reward offered to ten randomly selected participants, conditional on negative test results for syphilis and trichomonas. The primary outcome was combined HIV/HSV2 incidence after 36 months. Between August 2018-February 2019, 2,489 individuals screened for eligibility and 2,206 were enrolled in the trial and randomized. Participants were followed for up to 36 months; 1089 (49.4%) were lost to follow-up at endline and 1,117 were included in the primary intent to treat analysis (609 lottery, 508 control). At 36 months, there was no effect of the lottery intervention on the incidence of combined HIV/HSV2 (unadjusted RD: - 0.006, 95% CI - 0.05, 0.04; adjusted RD - 0.001, 95% CI - 0.05, 0.05). However, the results may have been affected by disruption from the COVID-19 pandemic, and unexpectedly high study attrition levels made it impossible to statistically rule out possible moderate-sized effects.