As part of a larger investigation of cancer in Uganda, we conducted a case-control study of Kaposi's sarcoma in human immunodeficiency virus-1 (HIV)-seronegative adults presenting at hospitals in Kampala. Cases comprised 117 HIV-seronegative patients with Kaposi's sarcoma and controls comprised 1,282 HIV-seronegative patients with a provisional diagnosis of cancer other than Kaposi's sarcoma. Study participants were interviewed about social and lifestyle factors, tested for HIV and, if there was sufficient sera, for antibodies against Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8 [HHV8]), using an immunofluorescent assay. Independent effects of these factors were identified using unconditional logistic regression, after adjusting for age group (<30, 30–44, 45+) and sex. Antibody status for KSHV was available for 68% (80) of cases and for 45% (607) of controls. Among cases, 78% (91) were male and 57% (66) were over the age of 35. Cases were more likely than controls to be from tribal groups other than the Baganda (p = 0.05), to have higher household incomes (p = 0.003), to have left their home region at younger ages (p < 0.001), to own goats or pigs (p = 0.02) and to rarely or never use shoes (p < 0.001). Similar results were obtained when analyses were restricted to cases and controls with anti-KSHV antibodies. The seroprevalence of KSHV was 79% (63/80) in those with Kaposi's sarcoma as compared to 50% (302/607) in those without (χ2 heterogeneity (1 df) = 21.0; p < 0.001) and the risk of the tumour increased with increasing anti-KSHV antibody titres (χ2 trend (1 df) = 29.7; p < 0.001). The risk of Kaposi's sarcoma is clearly linked to antibody status for KSHV, but it would seem that in Uganda other factors are also important in the development of the tumour. © 2002 Wiley-Liss, Inc.