Most of the PCNSL of immunocompetent patients are diffuse large B-cell lymphomas (DLBCL). They differ from systemic DLBCL in their outcome, a poor survival in most cases contrasting with a lack of systemic dissemination. Concerning their histogenic derivation, a germinal center B (GCB) cell origin has been hypothesized, based on BCL-6 expression and ongoing mutational activity. Using cDNA microarrays, two main prognostic subgroups have been described in systemic DLBCL: the favorable GCB-cell like subgroup and the activated-B cell like, characterized by a non-favorable outcome. These prognostic subgroups are defined accurately by immunohistochemistry, using a panel of GC B-cell (CD10, Bcl-6) and activation (MUM1/IRF4, CD138) markers. The goal of the present study was to determined the immunoprofile of PCNSLs and its potential prognostic significance by analyzing retrospectively 28 cases included in two clinical trials from the GOELAMS (Groupe Ouest Est des Leucémies et Autres Maladies du Sang). According to the pathological panel review, all cases were classified as DLBCL, not associated with Epstein-Barr virus as shown by in situ hybridization. Immunohistochemistry was performed for CD10, BCL-6 and MUM1/IRF4 and CD138 on paraffin-embedded sections. Labelings were interpreted independently by two pathologists without knowledge of clinical data with 10% increments. Cases were considered positive when positive tumor cells accounted for more than 30%. CD10 was expressed in 1 out of the 28 cases. BCL-6 was expressed in more than 30% of tumor cells in 15/28 cases (54%). Strong nuclear expression of IRF-4 was found in almost all cases (26/28; 93%) and none of the tested cases expressed CD138. Thus, only one case was subclassified in the favorable GCB-cell like subgroup (CD10+/BCL-6+/IRF4−/CD138−). The other cases, classified in the non favorable activated-B cell like prognostic subgroup. The latter may be divided in two patterns: an activated or “late” GC B-cell pattern (CD10−/BCL-6+/IRF4+/CD138-) and an activated non-GC pattern (CD10−/BCL-6−/IRF4+/CD138−) observed in 54% and in 42 % of the cases, respectively. This study shows that PCNSL display an relatively homogeneous immunoprofile, corresponding to an activated late GC or early post-GC stage of B cell maturation, different from that published in systemic DLBCL. This result may partly explain the usual poor prognosis of PCNSL and raises the question of considering PCNSL as a separate biological entity, distinct from systemic DLBCL.