Splenectomy has traditionally been considered as standard treatment for SMZL conferring a survival advantage over chemotherapy. However it carries significant complications, especially in elderly patients. The purpose of the present study is to evaluate the safety and efficacy of Rituximab for the treatment of SMZL. Fourteen patients with SMZL, diagnosed in our Department were treated with Rituximab. Diagnosis was established using standard criteria. Twelve received Rituximab as first line treatment at a median time of 2 months (1–120) after diagnosis. The remaining two received Rituximab after splenectomy. Four patients were symptomatic. Patients’ median age was 68 yrs (range 50–78) and four were male. All non-splenectomized patients had palpable splenomegaly before treatment. The median size of the spleen was 10 cm blcm (3–20 cm). 12/14 patients had anemia, 6/14 leukocytosis, 9/14 lymphocytosis, 4/14 leukopenia and 5/14 thrombocytopenia prior to treatment initiation. Rituximab was administered for six weekly cycles of 375mg/m2. 6/13 patients received maintenance treatment, starting at a median time of four months (range 2–7) after the completion of the six cycles. Maintenance was given as 375mg/m2 every two months. Complete clinical response was defined as disappearance of palpable splenomegaly. Complete hematologic response was defined as the restoration of all hematologic parameters to normal values and partial hematologic response as an improvement of abnormal values without complete normalization. Molecular remission was defined as PCR negativity for IgH rearrangement in patients with negative bone marrow biopsy. 11 of 11 non-splenectomized patients achieved a complete clinical response (the 12th patient is still under treatment and response cannot be evaluated). Symptomatic patients had resolution of disease/splenomegaly related symptoms. 8/13 (62%) patients achieved a complete hematologic response, including the two previously splenectomized patients and 5/13 (38%) a partial hematologic response. Anemia was resolved in 8/11 patients, leukocytosis in 6/6, leukopenia in 1/3 and thrombocytopenia in 4/4 patients. Bone marrow biopsy after treatment disclosed persistent but reduced infiltration in 6/10, disappearance of lymphomatous infiltration in 3/10 and remained unchanged in a single patient. 2/3 patients with negative bone marrow biopsy were in molecular remission, while one patient remained PCR positive after treatment. He subsequently received a second course of four weekly cycles and became PCR negative. No patient presented infectious complications after Rituximab administration. Infusion related side effects were easily treated with steroids, antihistamines and paracetamol. Two patients, who did not receive maintenance treatment progressed with reappearance of splenomegaly both at 7 months after completion of treatment and were retreated with six cycles of Rituximab. One of them had a second response and the other remained with stable disease. All patients are alive. Median follow up after treatment initiation is 16 months (range 1–22) and median response duration has not been reached. In conclusion, Rituximab is a safe and effective treatment for SMZL and can be considered an alternative to splenectomy as first line therapy. Maintenance may be important for consolidation of response.