The HIV pandemic spawned a global biomedical research effort which continues today. Because of multinational clinical studies, doctors and health officials possess more tools than ever before for the effective prevention and treatment of HIV/AIDS. The relationship between the United States and Sub-Saharan African nations features prominently within this global research effort. More specifically, many of the most significant HIV-related research findings emanate from clinical trials with a unique multinational configuration: the study protocol is largely designed and funded by American sources but executed at clinical research sites in Sub-Saharan African countries like South Africa and Zimbabwe. This thesis investigates the context and ethics of this configuration, with a focus on US-backed trials conducted in South Africa specifically. Using data collected from semi-structured interviews conducted at South African HIV clinical research sites, this thesis uncovers two significant ethical problems: insufficient benefits delivered to South African clinical trial participants, and informal processes occurring alongside formal protocol. By examining scope, effects, and implications of these problems, it becomes clear that although this research system delivers powerful results, there exists room for improvement.