This study offers the first systematic analysis of the impact of press-state relations, or media systems, on the HIV/AIDS news agenda in African news coverage. The premise is that media systems play a determining role in the degree to which journalists can independently advocate for social change when covering HIV/AIDS. Drawing on comparative research, four sub-Saharan countries were categorized into two media systems: Contained Democratic (South Africa, Nigeria) and Repressive Autocratic (Zimbabwe, Kenya). A sample of HIV/AIDS stories (n = 393) published from 2002–2007 in each country's leading Anglophone newspaper was content analyzed. Across all coverage, the topic of social costs was framed more for the responsibility borne by nongovernmental agents than governmental agents. In Contained Democratic media systems, however, story emphasis shifted toward government agents taking responsibility for addressing the social costs of HIV/AIDS. Prevention campaigns were framed more as progress than decline across all newspapers; however, campaigns were reported as being more efficacious in Contained Democratic systems than in Repressive Autocratic systems. No impact of media system on framing of medical developments was found. Results show the value of comparative analysis in understanding the agenda-setting process: with greater emphasis on positive efficacy and government initiative, the news agenda in Contained Democratic media systems can facilitate stronger positive societal-level responses than the news agenda in Repressive Autocratic media systems.