The dwindling international funding for HIV&AIDS, limited domestic resources and the growing need for HIV&AIDS services in low-income countries make the cost-minimization of HIV&AIDS services essential to address the shortage of funds. Previous HIV/AIDS studies have addressed the budget constraints using quantitative methods in economic evaluation. Transaction cost analysis in HIV&AIDS service implementation—guided by the Transaction cost economics (TCE) theory sources of costs— asset specificity, service measurability, and opportunism—have not been sufficiently analyzed in the literature, nor have qualitative approaches been applied. Guided by TCE theory, this study (1) characterized transaction complexity levels needed in HIV&AIDS prevention services to safeguard asset specificity and services measurability and avoid opportunism in Uganda, (2) compared the relative transaction costs across three modes of HIV&AIDS prevention services, and (3) assessed whether the HIV&AIDS prevention services mode with the least transactions costs matched the proposition of the transaction (TCE) theory to guide HIV&AIDS transactions design. Data was collected from October to December 2020 from three dominant HIV&AIDS prevention services modes in Rakai, Lira and Mukono in Uganda. These modes were: (1) “ Public sector provision” mode, (2) Community-led HIV&AIDS Initiative—CHAI mode, and (3) Determined, Resilient, Empowered, AIDS-free, Mentored and Safe—DREAMS mode. These modes corresponded to respective TCE theory provision mode constructs: “ Internal integration,”“ Partnership,” and “ Contracting out.” In each HIV& AIDS prevention services mode, the study conducted key informant interviews, a review of documents, and a focus group discussion. Transaction cost data were analyzed across the three modes based on TCE theory’s sources of transaction costs ( aspect specify, service measurability and opportunism). Safeguarding asset specificity and services measurability in Uganda required transactions characterized by mixed-level complexity whilst avoiding opportunism required transactions characterized by high-level complexity. Based on these transaction characteristics requirements, the “ partnership” (CHAI) was HIV&AIDS prevention service mode most matching the TCE theory for cost minimization in Uganda. The evidence further suggested that CHAI had the least complex transactions to safeguard asset specificity, deal with HIV&AIDS service measurability, avoid opportunism, and hence the lowest transaction cost levels. The “ partnership” (CHAI) was the least costly in dealing with asset specificity, service measurability and opportunism in Uganda and was the most aligned with the proposition of the TCE theory. The findings imply that the TCE theory can be used to guide HIV&AIDS prevention services provision in Uganda.