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It has been argued that women's economic vulnerability and dependence on men increases their vulnerability to HIV by constraining their ability to negotiate the conditions, including sexual abstinence, condom use and multiple partnerships, which shape their risk of infection. In the face of escalating infection rates among women, and particularly young women, many have pointed to the potential importance of economic empowerment strategies for HIV prevention responses. Global evidence suggests that the relationship between poverty and HIV risk is complex, and that poverty on its own cannot be viewed simplistically as a driver of the HIV epidemic. Rather, its role appears to be multidimensional and to interact with a range of other factors, including mobility, social and economic inequalities and social capital, which converge in a particularly potent way for young women living in southern Africa. To date, there have been few interventions that have explicitly attempted to combine economic empowerment with the goal of HIV prevention, and even fewer that have been rigorously evaluated. This paper explores how programmes such as microfinance, livelihood training and efforts to safeguard women's food security and access to property have begun to incorporate an HIV prevention focus. Although such circumscribed interventions, by themselves, are unlikely to lead to significant impacts on a national or regional scale, they are useful for testing cross-sectoral partnership models, generating practical lessons and providing a metaphor for what might be possible in promoting women's economic empowerment more broadly. Despite numerous calls to ‘mainstream AIDS’ in economic development, cross-sectoral responses have not been widely taken up by government or other stakeholders. We suggest potential reasons for limited progress to date and conclude by presenting programme and policy recommendations for further exploring and harnessing linkages between economic empowerment and HIV prevention in Southern Africa.