A case control study was undertaken during 1988 and 1989 within the framework of the LEPRA Evaluation Project (LEP)/Karonga Prevention Trail (KPT) in Karonga District, northern Malawi, to investigate whether HIV infection is a risk factor for clinical leprosy. Cases were newly ascertained, biopsy-confirmed, incident leprosy patients older than 14 years of age. Controls were selected from the computer data base on over 170,000 people who form the basis of LEP/KPT. They were matched for sex, age, and area of residence. HIV seropositivity rates were 1.8% (2/112) for incident leprosy cases and 2.4% (24/1011) for controls. The Mantel Haenszel odds ratio is 0.6 (95% confidence interval 0.1-3.3). Thus, no evidence for an association between HIV infection and leprosy incidence has been observed in this population. In a parallel investigation, an odds ratio of 7.4% (95% confidence interval 3.3-16.7) was found for 102 microscopy- and/or culture-confirmed, incident pulmonary tuberculosis cases in the same population during 1989, a result similar to those obtained elsewhere in Africa. Among leprosy relapses, 16.7% (2/12) were HIV positive.