We aimed to identify risk factors for Kaposi's sarcoma (KS) among HIV-positive patients and behaviors associated with human Herpesvirus 8 (HHV-8) infection, as well as to assess KS incidence and mortality rates longitudinally. To fulfill the first objective, a European case-control study was designed in the early 1990s (each KS case was matched to 2 controls with another AIDS indicative disease). After the discovery of HHV-8, serology testing enabled us to assess risk factors for KS development among HHV-8 and HIV-1 coinfected men who have sex with men (MSM), as well as risk factors for HHV-8 infection. HHV-8 seroprevalence was determined using a latent immunofluorescence assay. Relevant information was obtained by means of a questionnaire and medical charts review. Assessment of risk factors for KS development and HHV-8 infection was performed using conditional and unconditional logistic regression models, respectively. A low CD4 count was the only significant risk factor for KS. HHV-8 infection was most strongly linked to the number of life-time sex partners, and multiple body fluids such as saliva and semen are quite likely involved in sexual transmission. Longitudinal follow up showed a significant protective role for highly-active antiretroviral therapy (HAART) both on KS development and mortality of KS patients. Although more conclusive data from cohort studies are needed to better define specific transmission mechanisms for HHV-8, our results contribute to explain why KS incidence is higher among MSM, and the decreasing KS incidence trend observed in countries with universal access to HAART. © 2006 Wiley-Liss, Inc.