The introduction of rituximab for diffuse large B-cell lymphoma (DLBCL) has improved the disease's overall prognosis. However, relapse in the central nervous system (CNS) is still an issue. We investigated the prognosis and risk factors of CNS recurrence in DLBCL. A total of 403 patients who were diagnosed with DLBCL without CNS involvement between January 1996 and April 2007 at our institution were included in the study. Subsequently, 42 experienced CNS relapse. Clinical information was gathered by chart review. The median disease-free interval to CNS relapse was 625 days. The mean survival periods after relapse in the cases with CNS and extra-CNS involvement were 513 and 1,615 days, respectively (P = 0.0004). Multivariate analysis identified age >60 years (P = 0.031), involvement in two or more extranodal sites (P = 0.040), bone marrow involvement (P = 0.036), an elevated serum lactate dehydrogenase (LDH) level (P = 0.016), and treatment without rituximab before CNS relapse (P = 0.027) as independent predictors of CNS relapse. We have shown that cases of DLBCL occurring in advanced age, involving two or more extranodal sites or the bone marrow, or showing an elevation of LDH have a higher risk of CNS relapse. Rituximab may prevent CNS relapse by reducing the recurrence of DLBCL at all sites. An effective CNS prophylaxis strategy should be determined according to the risk assessment of CNS relapse.