Gender and sex lie at the heart of South Africa’s generalised and heterosexual epidemic. The stark feminisation of HIV in South Africa telescopes research, policy and interventions on to the socio-economic inequalities that make women particularly vulnerable to the impact of HIV and AIDS. There is a corresponding risk of reducing the complex and relational nature of gender down to a binary that positions women as victims and men as perpetrators. Accordingly, we seek to disrupt this dichotomy and point to the multiple ramifications of gender inequality for both men and women’s wellbeing in relation to HIV prevention, testing and treatment. The findings are drawn from a qualitative study conducted in Cape Town, South Africa, in 2007 and 2008. The researchers identified three main research groups and corresponding research methodologies to elicit particular information regarding the challenges faced by members of HIV/AIDS non-governmental organisations, medical doctors and people living with HIV. The research methods include: twenty-nine narrative interviews with HIV-positive men and women; three focus group discussions; and eight semi-structured interviews with medical doctors. The findings highlight the relational nature of gender, its intersection with a range of behavioural, social and physical drivers, and the various ways in which both men and women shape their own and each other’s health within the sexual relationship dyad. Constructions of tradition and masculinity that valorise unsafe sex emerged as a significant barrier to HIV prevention for both men and women, and deterred men from testing for HIV or accessing critical health care. Women accessed health care more readily than men, but they feared and experienced stigma from their sexual partners, which in turn undermined disclosure and safe sex, compromised antiretroviral adherence, and reinforced mixed infant feeding practices. This paper calls for a more nuanced understanding of gender dynamics that moves beyond the ‘victim/perpetrator’ dichotomy which lambasts men and pities women. Accordingly, it explores factors that may shift these dynamics and open up space for more constructive engagement that promotes both men and women’s health within the matrix of social, economic and emotional wellbeing.