Diffuse large B-cell lymphoma (DLBCL) of the gastrointestinal tract is heterogeneous, including mucosa-associated lymphoid tissue (MALT) origin and non-MALT, and they are indistinguishable. MALT lymphoma is a tumor of a post-germinal center (GC) memory B-cell origin, which is negative for Bcl-6 protein expression in low-grade but may become positive in high-grade tumors. Because Bcl-6 expression patterns in lymphoma of GC and non-GC B-cell origins have recently been characterized and CD10 is generally regarded as a specific marker for GC B cells, we critically evaluated gastric and small intestinal DLBCLs to see whether it is possible to identify tumor of GC B-cell origin by immunostaining in archival specimens. High-grade MALT lymphoma (H-ML) of the stomach (n = 20) was defined by the presence of a concomitant lymphoepithelial lesion and/or follicular colonization; and DLBCLs de novo, both gastric (n = 31) and intestinal (n = 21), were defined by the absence of the above features. Immunostaining for Bcl-6 and CD10 was done using formalin-fixed, paraffin-embedded sections and was examined independently by three pathologists. Staining for Bcl-6 was positive (>10% of tumor cells) in 55 of 72 cases. However, two distinct patterns were recognized among those positive: diffusely dense (>75%) and sporadic (<75%). The former was further characterized by a consistency of Bcl-6+ tumor cell density at any given area, resembling the staining pattern of the GC or follicular lymphoma (FL) (GC/FL pattern), whereas the latter was, besides less dense population, by variable density from area to area. The GC/FL pattern was observed in 36% and 38% of gastric and intestinal DLBCLs de novo, respectively, but in none of the gastric H-ML. CD10 was positive in 12 of 71 cases (17%), all coexpressing Bcl-6. CD10+ tumors were more frequent in the intestinal (33%) than in gastric DLBCLs ( approximately 15%). Significantly, CD10 expression was observed in three gastric H-MLs, including one that displayed a distinct lymphoepithelial lesion. In conclusion: 1). tumors showing a diffusely dense pattern of Bcl-6 expression should be distinguished from those showing a sporadic pattern; for the former most likely represents the tumor of GC B-cell derivation, and the latter non-GC, including MALT lymphoma; 2). tumor of GC B-cell origin thus defined accounted for about one third of gastric as well as intestinal DLBCLs de novo but none of the gastric H-ML; and 3). CD10 expression can be seen in MALT lymphomas and should not be used as the marker for GC B cells.