Some human cancers are caused by coinfections with two viruses. Here we focus on primary effusion lymphomas (PEL), which arise from coinfection of B cells with Kaposi’s Sarcoma–associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) and often are accompanied by systemic infections with human immunodeficiency virus (HIV). Both KSHV and EBV contribute to this oncogenesis of a rare B cell subset and HIV, by limiting the host immune response to coinfected cells, can too. Some of the mechanisms underlying the lymphomagenesis mediated by two tumor viruses are clear; some remain to be elucidated.