PROJECT SUMMARY/ABSTRACT While expansion of antiretroviral therapy (ART) coverage over the past two decades has significantly decreased mother-to-child, or “vertical,” transmission, progress has stagnated in recent years. To address the remaining 130,000 new infections among children each year, we must take a broader approach, promoting maternal ART coverage within the context of additional interventions. The key question is, which additional interventions will most benefit elimination of mother-to-child transmission (eMTCT) efforts while also being economically feasible for a country to implement? Simulation-based modeling and decision science have played an important role in evaluating the benefits and costs of HIV treatment and prevention strategies, in order to inform guidelines and policy decisions. We propose to apply these methods to guide eMTCT health policy in sub-Saharan Africa, where the majority of infant infections occur. Most decision science work in this area has focused on adult HIV, while the limited number of eMTCT studies have largely focused on interventions downstream of ART initiation, despite the potential for interventions upstream of ART initiation to have significant impact. We have identified an eMTCT toolbox of six interventions that span the entire reproductive continuum, from preconception to postpartum: access to contraception to more safely time pregnancies, pre-exposure prophylaxis to prevent HIV infection among pregnant and breastfeeding women (PBFW), HIV re-testing to ensure prompt ART initiation among PBFW who acquire HIV, and long-acting ART, mentor mother programs, and viral load testing to increase viral suppression rates among PBFW who initiate ART. Implementing all six interventions at full-scale is ideal but not feasible given resource limitations. To identify implementation priorities, we will evaluate the population-level effectiveness and cost-effectiveness of each of these interventions, alone and in different combinations or “portfolios” of various sizes. Because the cost-effectiveness and affordability of an intervention will depend on country-specific factors, including economic resources, demographics, epidemic characteristics, and eMTCT progress to date, we will tailor our evaluation to the specific country contexts of Kenya, Nigeria, and Botswana. These three African countries all have a high HIV burden but also represent diversity in key relevant characteristics, making them useful case studies for a wide range of other African countries. Our findings from this comprehensive eMTCT intervention analysis will provide urgently-needed support for eMTCT policymaking in each of our three focus countries, paving the way for a new frontier in eMTCT progress in these and other African settings.