INTRODUCTION: In patients with low-grade non-Hodgkin's lymphoma, rituximab (MabThera) produces infusion-related toxicity, including fever, rigors, and chills in greater than 50% of those treated. The majority of these reactions are grade 1 or 2. MATERIALS AND METHODS: In the GELA study LNH98-5, a total of 400 elderly patients with previously untreated diffuse large B-cell lymphoma were randomized to treatment with CHOP or with rituximab plus CHOP (R-CHOP). In a detailed investigation of biological events which may be associated with adverse reactions specific to rituximab infusion, a subgroup of 55 patients (26 in the CHOP group and 29 in the R-CHOP group) were selected for measurement of several biological parameters at baseline and at 1, 4 and 8 h (H1, H4 and H8, respectively) after commencing therapy. For 27 patients, measurements included cytokine and complement levels. RESULTS: Baseline demographic and disease characteristics were similar for patients in both treatment groups. Compared with the CHOP treatment group, patients in the R-CHOP group had significantly higher post-treatment changes in neutrophil, lymphocyte, and monocyte counts, LDH levels, C3a levels, and TNF-alpha levels. In the R-CHOP group, neutrophil levels increased at H4 (P<0.05), lymphocyte levels decreased at H1 (P<0.05), H4 (P<0.001) and H8 (P<0.05), monocytes levels decreased at H1 (P<0.01), LDH levels increased at H4 (P<0.05) and H8 (P<0.01), and C3a decreased at H1 (P<0.01). The most statistically significant changes were observed for TNF-alpha levels: Mean values of TNF-alpha increased more than 250% at H1 and H4 and were still increased by 170% at H8 (P<0.001 at all timepoints). Since only six of the 55 evaluated patients had severe adverse events, it was not possible to correlate severe toxicity with these biological variations. CONCLUSION: This analysis demonstrates that rituximab infusion was rapidly followed by activation of complement, B-lymphocyte cytolysis, and TNF-alpha release.