Rituximab improves outcome for patients with systemic diffuse large B-cell lymphoma (DLBCL) and has therefore become a standard component of the treatment of this disease. However, it is unclear whether rituximab is efficacious in patients with primary CNS lymphoma (PCNSL), a rare DLBCL variant, also. The purpose of this study was to evaluate the effect of rituximab on the complete response (CR) rate after chemotherapy with methotrexate (MTX) and ifosfamide (IFO) of patients with PCNSL. This is a retrospective, observational, single-center trial analyzing 36 consecutive patients with newly diagnosed, CD-20-positive PCNSL who were treated primarily with chemotherapy between March 2007 and December 2010. We compared 19 patients who were treated with MTX and IFO with 17 patients who were treated with the same regimen plus rituximab. The addition of rituximab to MTX and IFO was correlated with a significant increase in the CR rate (100.0 vs. 68.4 %, p = 0.02). Furthermore, six-month progression-free survival was significantly higher for the rituximab group (94.1 vs. 63.2 %, p = 0.04). Toxicity did not differ significantly between the groups. Our results indicate that rituximab might be efficacious in the treatment of PCNSL and support addition of this drug to current treatment protocols until data from randomized controlled trials becomes available. Immunochemotherapy with MTX, IFO, and rituximab seems to have excellent activity as induction chemotherapy and should be further tested in prospective trials.