In this study the authors explored the value of immunostaining for follicular center B-cell markers, BCL-6 and CD10, in paraffin sections as a tool for the differential diagnosis of B-cell lymphomas. The cases studied comprised reactive lymphoid hyperplasia (RLH; n = 19), follicular lymphoma (FL; n = 50), low-grade mucosa-associated lymphoid tissue (MALT) lymphoma (n = 24), mantle cell lymphoma (n = 19), splenic marginal zone lymphoma (n = 13), diffuse large B-cell lymphoma (DLBCL; n = 54), Burkitt's lymphoma (BL; n = 20), nodular lymphocyte predominance Hodgkin's disease (NLPHD; n = 16), and classic Hodgkin's disease (CHD; n = 13). In RLH, CD10 and BCL-6 were expressed almost exclusively by the follicular center cells. In contrast in FL, the expression of CD10 (39/50) and BCL-6 (34/36) was seen in both follicular and interfollicular neoplastic B cells. Marginal zone/MALT lymphomas and mantle cell lymphoma were always negative. In DLBCL the expression was variable for both CD10 (21/54) and BCL-6 (39/47), with some tumors, including cases of transformed follicular lymphoma (9/10), coexpressing CD10 and BCL-6, and others expressing only BCL-6, and a small group expressing neither marker, possibly reflecting the underlying primary pathogenetic events such as the rearrangement of BCL-2 or BCL-6 genes. BL was always both CD10 and BCL-6 positive. In NLPHD the L&H cells expressed BCL-6 (11/13) but not CD10, whereas in CHD BCL-6 expression was seen in half of the cases. This study demonstrates that both CD10 and BCL-6 are reliable markers of follicular center B-cell differentiation. CD10 and BCL-6 immunostaining have an important role in differential diagnosis of FL from RLH and other low-grade B-cell lymphomas. The results also suggest that a CD10/BCL-6 expression pattern may be helpful in identifying main subsets of DLBCL. However, additional studies comparing genotype with immunophenotype are required.