BACKGROUND: Malaria and HIV are two of the most important diseases facing Africa. It remains uncertain whether HIV-related immunosuppression adversely affects the clinical outcome of malaria. OBJECTIVE: To measure the association between HIV status and outcome from malarial infection in adults living in a region of unstable malaria transmission. DESIGN: Observational cohort study. SETTING: Four community clinics and the Government hospital in Hlabisa district, KwaZulu-Natal, South Africa; a region of high HIV prevalence. METHODS: Consecutive febrile adults were screened for malaria with a rapid antigen test. Those with malaria provided blood spots for HIV testing, a thick blood film for confirmation of malaria and clinical data. Outcome was established following management according to South African government guidelines. RESULTS: Malaria was microscopically confirmed in 613. HIV prevalence was 29.9% (180/613); 110 (18%) had severe/complicated malaria and 28 (4.6%) died. HIV-infected patients were more likely to vomit or be confused and were more likely to be admitted to hospital (P = 0.05). In patients admitted to hospital, HIV infection was associated with severe/complicated malaria [adjusted odds ratio (OR) 2.3; 95% confidence interval (CI), 1.4-3.9] and with death (OR 7.5; 95% CI, 2.2-25.1). Acidosis and coma were also strong independent risk factors for death. CONCLUSION: HIV infection had an unexpectedly large association with the outcome of falciparum malaria in a region of unstable transmission. Both diseases are widespread in Africa and these results add to the body of knowledge suggesting an interaction of significant public health importance between HIV and malaria in Africa.