In this randomized open-label trial, 449 non-pregnant cisgender women (18 to 30 years old) taking TDF/FTC daily as PrEP were enrolled to receive doxycycline PEP and quarterly STI testing and treatment.  Over 12 months of follow-up, participants completed quarterly questionnaires and received weekly short message surveys eliciting information on sexual exposures and doxycycline use.  The median number of doses/month was 4 (IQR 0-8), number of sex acts/month was 4 (IQR 2-8), and number of partners/past quarter was 1 (IQR 0-2).  Over 90% of quarterly timeline follow-back calendars indicated at least 80% doxycycline coverage after condomless sex in the previous 2 weeks, with most doses taken within 24 hours.  In over 90% of weekly SMS surveys, 55% of participants in the doxycycline group reported taking it at least as many days as they had sex.  Among 50 participants randomly selected for hair analyses, medication was detected in at least one visit in 28 (56%); across quarterly visits medication was detected in 58/200 (29%) of visits.  After excluding visits in which doxycycline was on hold, medication was detected in 58/178 (32.6%).  25.1 incident STIs per 100 person-years occurred in the doxycycline-PEP group versus 29.0 in the standard-of-care group.  Of the total 109 incident STIs, 85 (78.0%) were C. trachomatis, 31 (28.4%) N. gonorrhoeae, and 1 (0.9%) T. pallidum.  Overall, quarterly STI incidence was not significantly lower with doxycycline PEP: relative risk 0.88 (95% CI, 0.60 to 1.29).  Subgroup analyses incorporating age, contraception use, history of transactional sex, and STI detection at baseline yielded similar results.  No serious adverse events occurred, and nausea was the most common (7.2%) side effect.  Social harms were reported four times among three participants because of unintentional disclosure of doxycycline PEP use.