Individuals infected with HIV are at increased risk of developing aggressive non-Hodgkin's lymphoma with a worse prognosis than those similarly afflicted without HIV infection. The underlying genetic differences in tumor behavior between these two groups are not known. We explored the hypothesis that lymphomas from HIV-positive individuals have distinct somatic genetic changes that may provide clues to the genetic basis of disease progression and outcome. Genome-wide DNA copy number alterations (CNAs) in primary tumors from 14 HIV-positive and 11 HIV-negative patients with diffuse large B-cell lymphoma (DLCL) were quantified using comparative genomic hybridization (CGH). Tumors from HIV-positive patients displayed fewer regional DNA-CNAs than those from patients who did not have HIV. When CNAs were present, they occurred at lower frequency in HIV-positive patients. Gains at chromosomes 8q and Xp were the most frequent changes in the HIV-negative group, and gains on 2p and 12q were common in the combined HIV-positive and HIV-negative groups. No alteration was specific to AIDS-related DLCL. These data suggest that fewer somatic genomic changes are needed for progression to DLCL in HIV-immunocompromised hosts, and that other factors, such as reduced immune surveillance, may contribute to neoplastic progression.