The purpose of this comparative study was to evaluate the response of primary splenic low-grade non-Hodgkin's lymphomas (NHL) to chemotherapy, splenectomy, and chemotherapy combined with splenectomy in order to elaborate the optimum treatment modality. A total of 104 patients (age range: 15-82 years) with primary low-grade B-cell NHL of the spleen were comprised by our study. Stage IV disease was determined in 102 (98.1%) cases. Regarding the treatment modality, splenectomy was performed in 14 patients, early splenectomy and single-agent chemotherapy in 15, early splenectomy and combined chemotherapy in 19, single-agent chemotherapy in 23, and combined chemotherapy in 33. In the above-mentioned order, complete remission rate was following: none, 40.0, 31.6, 21.8, and 18.2%. Partial remissions were achieved in 85.7, 46.7, 57.9, 30.4, and 69.7% of cases, respectively. The median remission duration turned out to be longer (74.5 months) in the group of patients with complete remissions attained by means of splenectomy and combined chemotherapy. Local relapses in the spleen developed in 19 (72.7%) patients treated with combined chemotherapy and in 9 (90.0%), who had undergone single-agent chemotherapy. The 5-year overall survival was 54.4% after splenectomy, 39.4% after single-agent chemotherapy, and 37.1% after combined chemotherapy, being significantly higher (P <0.05) after splenectomy and single-agent chemotherapy (67.2%), and splenectomy followed by combined chemotherapy (64.7%). Early splenectomy combined with chemotherapy is the optimum treatment option for primary low-grade NHL of the spleen because of the superiority in complete remission rate, remission duration, and in overall survival rate. Splenectomy leads to somatic compensation of patients, makes impossible local relapsing in the spleen, prevents continuous dissemination from the primary tumor site, and mostly corrects cytopenias, creating better conditions for chemotherapy.