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), human T-lymphotropic virus types I and II (HTLV-I/-II), 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) enrolled and completed prospective follow-up of more than 2500 HCV-exposed persons with hemophilia. Testing of the cohort with newly developed Taq-Man PCR assays for detection and quantification of HCV and HIV RNA was also completed. A public website was established (https://mhcs-ii.rti.org) with background information and data analysis procedures. Among HIV-uninfected participants, spontaneous clearance of HCV was found to be associated with infection at a very young age and in relatively recent calendar years. In a collaboration, AIDS progression rate was related to differences in several genes related to immunity. A four-year case-control study of classical (non-AIDS) Kaposi sarcoma and KSHV infection thorughout the island of Sicily (where cKS and KSHV are endemic) was completed. Analyses will focus on the risk of cKS and KSHV with smoking, skin hygiene, medication use, contact with plants, host genetics, and other factors. Among children with HTLV-I infection, antibody titer was found to increase for the first year after infection. HTLV-I proviral load increased for an additional year, but only in children with eczema, which may be an indicator of higher risk of disease (adult T-cell leukemia/lymphoma and tropical spastic paraparesis) during adulthood.Collaborations with private and academic laboratories were established to foster development of detection methods for known or possible cancer-associated viruses.