To determine whether HIV-1 infection and HIV-1-related immunosuppression were risk factors for severe malaria in adults with some immunity to malaria, we conducted a case-control study in Luanshya, Zambia, during December 2005-March 2007. For each case-patient with severe malaria, we selected 2 matched controls (an adult with uncomplicated malaria and an adult without signs of disease). HIV-1 infection was present in 93% of case-patients, in 52% of controls with uncomplicated malaria, and in 45% of asymptomatic controls. HIV-1 infection was a highly significant risk factor for adults with severe malaria compared with controls with uncomplicated malaria (odds ratio [OR] 12.6, 95% confidence interval [CI] 2.0-78.8, p = 0.0005) and asymptomatic controls (OR 16.6, 95% CI 2.5-111.5, p = 0.0005). Persons with severe malaria were more likely to have a CD4 count <350/microL than were asymptomatic controls (OR 23.0, 95% CI 3.35-158.00, p<0.0001).