The purpose of this study was to test the efficacy and safety of thymostimulin (TS) administered in addition to conventional chemotherapy in patients with intermediate- and high-grade non-Hodgkin's lymphoma (IG, HG-NHL). A total of 150 patients with newly diagnosed IG- or HG-NHL were entered in a multicenter trial to compare the effectiveness of two different third-generation regimens (MACOP-B versus ProMACE-CytaBOM) and were randomized to receive chemotherapy (CT) alone or CT + TS. In both regimens doxorubicin was replaced by a 20% higher dose of epidoxorubicin. TS was administered i.m. at a dose of 1 mg/kg daily on days 22-28 of each drug course to patients treated with ProMACE-CytaBOM, and on days 22-29, 50-57, and 77-85 to patients treated with MACOP-B. There were 134 fully evaluable patients: 68 treated with CT alone and 66 treated with CT + TS. Patients treated with CT + TS had a higher complete remission (CR) rate compared to patients given CT alone (59.1% vs 42.4%; P = .05). CR were significantly higher for patients treated with CT + TS in the groups with IG-NHL (P = .01), in those aged less than 60 years (P = .05), with good performance status (P = .05), and normal hemoglobin levels (P = .05). Four-year survival rates are 64.5% for patients treated with CT + TS and 43.0% for those treated with CT alone (P = .30). No difference between the two treatment arms have been observed as regards drug-related toxicity and the number and severity of infectious episodes. The use of TS during the 7 days before chemotherapy has been associated with a significantly superior CR rate. The advantage of CT + TS was mostly obtained in patients with IG-NHL, and those with good performance status or normal hemoglobin levels. In these patients TS may have potentiated the host reactions against the tumor, leading to an increase in NK activity and the production of cytokines. This postulated increase in the effectiveness of chemotherapy after TS might also explain the absence of the expected myeloprotective action.