There is widespread evidence that male partners influence women's ability and willingness to join HIV prevention trials and to use female-controlled prevention strategies such as microbicide gels. VOICE-C was an ancillary study to the Microbicide Trials Network's VOICE trial at the Johannesburg site that explored social and structural factors influencing women's use of study tablets and vaginal gel. Qualitative data were analyzed from 102 randomly-selected VOICE participants interviewed through in-depth interviews (IDI, n = 41); ethnographic interviews (n = 21) or focus group discussions (FGD, n = 40) and 22 male partners interviewed in 14 IDI and 2 FGD. Male partners' "understanding" pervaded as a central explanation for how male partners directly and indirectly influenced their female partners' trial participation and product use, irrespective of assignment to the gel or tablet study groups. The meaning behind "understanding" in this context was described by both men and women in two important and complementary ways: (1) "comprehension" of the study purpose including biological properties or effects of the products, and (2) "support/agreeability" for female partners being study participants or using products. During analysis a third dimension of "understanding" emerged as men's acceptance of larger shifts in gender roles and relationship power, and the potential implications of women's increased access to biomedical knowledge, services and prevention methods. Despite displays of some female agency to negotiate and use HIV prevention methods, male partners still have a critical influence on women's ability and willingness to do so. Efforts to increase their understanding of research goals, study design and products' mechanisms of action could ameliorate distrust, empower men to serve as product advocates, adherence buddies, and foster greater adherence support for women in situations where it is needed. Strategies to address gender norms and the broader implications these have for female-initiated HIV prevention should likewise be integrated into future research and program activities.