Primary effusion lymphoma is an aggressive B-cell lymphoma most commonly diagnosed in HIV-positive patients and universally associated with Kaposis sarcoma-associated herpesvirus (KSHV). Chemotherapy treatment of PEL yields only short-term remissions in the vast majority of patients yet efforts to develop superior therapeutic approaches have been impeded by lack of animal models that more accurately mimic human disease. To address this issue we developed a direct xenograft model, UM-PEL-1, by transferring freshly-isolated human PEL cells into the peritoneal cavities of NOD/SCID mice without in vitro cell growth. We utilized this model to show that bortezomib induces PEL remission and extends overall survival of mice bearing lymphomatous effusions. Transcriptome analysis by genomic arrays revealed that bortezomib downregulated cell cycle progression, DNA replication, and Myc-target genes.