The choice of suitable study populations in which to conduct large-scale phase III HIV prevention trials is a fundamental issue for communities, researchers, sponsors and donor organizations. In many developed and developing countries, such trials are feasible only among vulnerable, disadvantaged communities at high-risk of HIV and sexually transmitted infections, where high HIV incidence rates make randomised controlled efficacy trials feasible but where poverty, social exclusion, illiteracy, stigma and powerlessness mean ethical considerations are paramount. In such settings, preliminary feasibility studies are considered essential to inform the design of future phase III efficacy and safety trials. Researchers typically frame their assessment of feasibility within an ‘epidemiological paradigm’, focusing on a limited number of key biomedical outcome parameters to guide decision making. These include HIV, STI and pregnancy incidence; and the feasibility of recruiting and retaining sufficient numbers of subjects from a given study population. This Thesis argues that a more comprehensive assessment of feasibility, which combines epidemiological factors with other key constructs such as ethics and social justice, is critical to the successful conduct of high quality and ethically sound HIV prevention trials among vulnerable at-risk study populations in Africa. This work is based on a combination of epidemiological, applied social science and participatory action-orientated research conducted during a microbicide trial feasibility study and an on-going phase III randomised placebo-controlled efficacy and safety trial of the candidate vaginal microbicide PRO2000/5 Gel (Indevus Pharmaceuticals, USA) that I coordinated as the Clinical Site Principal Investigator in Tanzania from November 2002 until March 2007, and for which I remain a Co-Investigator. All fieldwork was carried out in Mwanza City, in the Lake Victoria basin region of northwest Tanzania, among an occupational cohort of women working in bars, guesthouses, hotels and other food outlets and recreational facilities. Some women in this occupational group are known to periodically engage in transactional and commercial sex to supplement their income and are therefore considered to be at increased risk of HIV and sexually transmitted infections, and to represent a potential study population for future microbicide and other HIV prevention trials.