ABSTRACT Significant morbidity and health care costs are associated with Chlamydia trachomatis (CT) and Mycoplasma genitalium (MG) infections. Each is associated with male and female reproductive tract syndromes, yet each presents unique challenges for control. CT is the most commonly reported nationally notifiable condition in the US and is a known cause of pelvic inflammatory disease (PID) and infertility. Despite longstanding control programs, CT rates are at an all-time high and the utility and cost-effectiveness of CT prevention efforts are debated. As most CT infections are asymptomatic, our current understanding of the epidemiology and the effectiveness of CT control programs has depended entirely on case detection through screening, which is only targeted to select populations (women <25 years and other high risk persons). Much less is known about CT in women ≥25 who are infrequently screened, and screening is not recommended for men who have sex with women (MSW). These major gaps in our understanding have limited our ability to effectively target CT prevention programs to men and women at highest risk of infection. MG is a more recently emerged pathogen, responsible for 20-30% of male urethritis. There is no national MG surveillance and, despite general agreement that MG causes male urethritis, there is no consensus about whether it causes sequelae in women. Limited population based estimates of urogenital MG prevalence exist, yet prevalent infections are often a poor predictor of lifetime experience of PID and infertility and permit only partial understanding of population-level epidemiology. Antimicrobial resistance (AMR) in MG is rapidly expanding - MG is one of three bacteria on the CDC's 2019 Watch List of AMR threats - but AMR prevalence estimates are derived from high-risk STD clinic populations and there are no nationally representative data. A better understanding of the population-level epidemiology of CT and MG is critical to improving control efforts for each. To achieve this, we will conduct a seroepidemiologic study in the National Health and Nutrition Examinations Survey (NHANES) 2017-2018 cycle, using a novel serologic assay for CT that differentiates IgG isotypes to distinguish recent from distant infection, and a more sensitive and specific seroassay for MG. We will also identify AMR in urine specimens from MG-positive persons in NHANES 2017-2018. Finally, we will develop an individual-based CT and MG transmission dynamics model. Using these outputs, we will (1) estimate the lifetime prevalence of CT in US men and characterize factors associated with recent versus past infection among men and women; (2) estimate the seroprevalence and correlates of MG infection in US men and women, determine the association between prior MG infection and self-reported PID and infertility, and estimate prevalence and correlates of macrolide and quinolone resistance in MG; (3) evaluate the impact of CT and MG screening scenarios on reprod...