The optimal treatment strategy and outcome of non-gastric marginal zone lymphoma (MZL) remains undefined. The role of rituximab and fludarabine in MZL has not been critically appraised and compared with conventional chemotherapy. We retrospectively analyzed 81 consecutive patients with non-gastric MZL (mucosa-associated lymphoid tissue lymphoma, n=66; splenic MZL, n=11; nodal MZL, n=4). As a group, the treatment results were favorable, with an overall response rate of 87% and a complete response (CR) rate of 73%. The CR rate was similar for conventional chemotherapy, and rituximab- and fludarabine-containing regimens. However, the relapse rate was significantly decreased in rituximab- and fludarabine-containing regimens. The use of rituximab and fludarabine was associated with acceptable side effects. For splenic MZL, splenectomy was significantly associated with a superior CR rate. Early stage, good performance status, and low international prognostic index risk scores significantly impacted on CR rate and survivals. Rituximab and fludarabine were safe for non-gastric MZL and resulted in more durable remissions.