ABSTRACT Cancer incidence, mortality, and disparities between rich and poor are projected to rise at staggering rates. It is estimated, for example, that cancer will kill one million Africans each year by 2030, with cervical cancer accounting for the most cancer deaths in African women. Global efforts to eliminate cervical cancer are currently focused on expanding access to HPV vaccination and cervical cancer screening. However, these efforts lack equal investment in treatment of precancerous cervical intraepithelial neoplasia grade 2/3 (CIN2/3), particularly among HIV-infected women. This gap leaves a generation of HIV-infected women at high risk of persistent/recurrent CIN2/3 and progression to cervical cancer because standard treatment for CIN2/3 (excision or ablation) is far less effective in this population. The need for novel treatment approaches for CIN2/3 in HIV- infected women is therefore substantial. The central hypothesis of our proposal is that topical 5-fluorouracil (5FU), a widely available low-cost generic drug, can be repurposed as a patient-controlled, adjuvant treatment for CIN2/3 after surgical excision to reduce the risk of persistent/recurrent CIN2/3 and progression to cervical cancer among HIV-infected women. Our overarching goal is to build on U.S. efficacy studies and test the acceptability and feasibility of combination treatment for CIN2/3 (i.e., surgical excision followed by self- applied adjuvant 5FU) in a low-resource setting. First, we will explore South African perspectives on current cervical cancer prevention strategies and identify barriers to and facilitators of combination treatment in the local context. We will accomplish this through a series of focus groups and in-depth interviews with diverse stakeholders (HIV-infected women, male partners, healthcare personnel). Second, and informed by our formative research, we will conduct a feasibility trial of the combination treatment strategy to determine safety, tolerability, adherence, and retention. We will randomize 180 HIV-infected women with CIN2/3 who will undergo loop excision (LEEP) followed by self-apply 5FU versus placebo (8 doses, once every 2 weeks). Women will be followed for 24 weeks. Third, to better understand the immune response to combination treatment in HIV-infected women, we will assess changes in genital HIV-1 shedding and local immune activation associated with surgical excision followed by 5FU/placebo. Our study will be conducted in South Africa, where more than 4 million women are living with HIV and women’s lifetime risk of cervical cancer is among the highest in the world. If successful, our findings will have broad relevance for HIV-infected women in both resource-rich and resource-poor regions worldwide, including rural and remote areas of the U.S.