To study the pathogenesis of malignant lymphomas (ML) in intravenous drug-abuser HIV-infected patients, we analyzed 19 cases of reactive lymphadenopathy (LAS) and 10 cases of ML. Clonality and differences in characteristics of these lymphoproliferative disorders were investigated by immunohistochemical and Ig and TCR gene rearrangement analyses. Rearrangements at the c-myc locus and presence of HIV and EBV viral genomes were also investigated. Four out of the five non-Hodgkin's lymphomas (NHL) analyzed were high-grade extranodal ML and were found to derive from precursor B cells. Monoclonal cell expansions were also detected in 2 cases of LAS. These cell expansions also consisted of precursor B cells. HIV genome was not detected in any of the samples tested and was therefore considered not to be involved as an etiological agent in these lymphoproliferative disorders. EBV genome was present in a clonal episomal form in the five Hodgkin's disease (HD) specimens tested. This finding suggested that a clonal cell population harboring the EBV viral genome must be present in HDs, pointing to a possible etiological relationship between EBV and HD in HIV-infected patients.