The purpose of this report is to document and compare the presenting clinical and laboratory findings of 38 patients, all intravenous drug abusers, with pathologically documented persistent generalized lymphadenopathy (PGL), and of 50 patients with AIDS-unrelated malignant lymphoma (30 with Hodgkin's disease and 20 with non-Hodgkin's lymphoma). All patients, aged 40 years or less, consecutively seen since May 1984 in a single institution in Italy, have prospectively undergone a similar clinico-pathologic approach. In addition to a history of intravenous drug abuse and HIV serology, the results indicate that a history of infection in the previous year, night sweats, weight loss, generalized lymphadenopathy, beta 2 microglobuline, transaminase, T4/T8 ratio less than 1, and polyclonal hypergamma-globulinemia significantly increased among PGL patients compared with patients with AIDS-unrelated malignant lymphoma. In contrast, patients with malignant lymphoma had a significant increase in mediastinal lymph nodes, sedimentation rate, LDH, fibrinogen and anemia. Therefore, at this time of an AIDS epidemic, after histologic diagnosis of reactive lymphadenopathy has been performed in young patients presenting with generalized lymphadenopathy, a request for a second biopsy and other invasive procedures may be avoided if clinical and laboratory data suggest a PGL syndrome. If not already performed, HIV antibody detection should be carried out in this setting.