Lymphoplasmacytic lymphoma (LPL) is an indolent lymphoma with moderate sensitivity to conventional chemotherapy. This study investigated whether the addition of rituximab to standard chemotherapy improves treatment outcome in LPL and the subgroup of LPL patients fulfilling the criteria of Waldenstroem's macroglobulinemia (WM). A total of 69 patients with previously untreated LPL were enrolled into the trial; 64 patients were evaluable for treatment outcome. In all, 48 of the 64 LPL patients fulfilled the criteria of WM. Patients were randomly assigned to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, n=34) or CHOP (n=30). R-CHOP resulted in significantly higher overall response (OR) rate (94 vs 67%, P=0.0085) in the LPL patients and in the WM subgroup (91 vs 60%, P=0.0188). With a median observation time of 42 months, R-CHOP induced a significantly longer time to treatment failure (TTF) with a median of 63 months for R-CHOP vs 22 months in the CHOP arm in the LPL patients (P=0.0033) and in the WM subgroup (P=0.0241). There was no major difference of treatment-associated toxicity between both treatment groups. These data indicate that the addition of rituximab to front-line chemotherapy improves treatment outcome in patients with LPL or WM.