In several studies of primary central nervous system lymphoma (PCNSL), deep-site involvement of the brain, as well as age and performance status (PS), were found to be independent prognostic factors. In immunocompetent patients, most primary central nervous system lymphomas (PCNSL) are diffuse large B-cell lymphomas (DLBCL), and recent studies have shown that Bcl-6 would be a favorable prognostic biomarker in PCNS-DLBCL. The objective of this study is to evaluate the clinical importance of the central nervous system (CNS) involvement pattern combined with Bcl-6 expression in PCNS-DLBCL patients. This study included 65 immunocompetent patients with PCNS-DLBCL who underwent treatment with high-dose methotrexate with whole-brain radiotherapy. Immunochemistry was performed for the Bcl-6 and Ki-67 antigens. Forty-four patients were male and 21 patients were female, with median age of 59 years. During the median follow-up period of 26 months, progression-free survival (PFS) was 25% and overall survival (OS) was 31%. Of 65 cases that could be subclassified, 31 patients were Bcl-6 positive and 34 patients were negative. Deep-site involvement of the brain was observed in 31 patients. The Bcl-6-positive group and the group having non-deep-site involvement of the brain were associated with favorable progression-free survival (PFS) (P < 0.001; P < 0.001) and overall survival (OS) (P = 0.001; P < 0.001). Results of univariate analysis showed that age above 60 years, Eastern Cooperative Oncology Group (ECOG) PS above 2, elevated lactate dehydrogenase (LDH) state, complete response (CR), and Bcl-6-positive and deep-site involvement were prognostic factors associated with PFS and OS. Results of multivariate analysis revealed that age above 60 years, ECOG above 2, elevated LDH state, Bcl-6 positivity, and deep-site involvement were independent prognostic factors for prediction of outcome. According to the combined prognostic value of Bcl-6 expression and the deep-site involvement pattern, the subgroup having Bcl-6-positive non-deep-site involvement of the brain showed more favorable PFS and OS than the other subgroups (P < 0.001, P < 0.001), whereas differences of survival among the other three subgroups were not significant (P = 0.054, P = 0.056). Bcl-6 positivity was found to be an independent prognostic factor for survival. Bcl-6 expression was associated with higher PFS and OS in patients having non-deep-site involvement. However, this was counteracted in the group of patients having deep-site involvement of the brain.