This project is a comprehensive, multidisciplinary effort to understand the natural history and modes of transmission of viruses and other infectious agents that are associated with cancer. With numerous intramural and extramural laboratory, clinical, and epidemiologic collaborators, and a core of prospective cohort and case-control studies, the effort is focused on human immunodeficiency virus (HIV), hepatitis C virus (HCV), and Kaposi sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8 or HHV-8). The Second Multicenter Hemophilia Cohort Study (MHCS-II) has enrolled and begun prospective follow-up of more than 2000 HCV-exposed persons with hemophilia. Testing of the cohort has been initiated with newly developed Taq-Man PCR assays for detection and quantification of HCV and HIV RNA have been developed and with a newly developed sequence-based method to determine HCV genotype. Initial analyses suggest that spontaneous clearance of HCV is associated with infection at a very young age and with infection via plasma cryoprecipitate rather than clotting factor concentrate. Analyses of data from the preceding first MHCS show that non-Hodgkin lymphoma risk is very strongly related to HIV infection and older age but not to HCV or hepatitis B virus (HBV) infection. In contrast, hepatocellular carcinoma risk is strongly related to HCV infection and older age, HIV infection, or HBV infection. Use of alcohol, acetaminophen, and non-steroidal anti-inflammatory drugs, all of which may be hepatotoxic, is generally low. In an extramural collaboration, HBV clearance was significantly more likely for participants with HLA genotype A*0301 or DRB1*1302 and for those without B*08. Among HIV/KSHV co-infected homosexual men in a prospective cohort study conducted during 1982-1999, risk for HIV/AIDS-associated Kaposi sarcoma was now found to be increased 11.7-fold [95% confidence interval (CI) 1.8-76] with detection of KSHV viremia. Without HIV, risk for classical (non-AIDS) Kaposi sarcoma was markedly reduced with cigarette smoking [odds ratio (OR) 0.23, 95% CI 0.12-0.44] and increased with use of topical corticosteroid cream or ointment (OR 2.73, 95% CI 1.35-5.51), history of asthma (OR 2.18, 95% CI 0.95-4.97), and bathing or showering less than twice per week (OR 1.85, 95% CI 1.04-3.33). Laboratory and field studies to clarify these associations are in progress.