Immunoreactivity for CD23, a B-cell activation antigen, was compared in 22 cases of B-cell small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL) and 15 cases of mantle cell lymphoma (MCL) (intermediate lymphocytic lymphoma or centrocytic lymphoma) to determine if the presence of this antigen can be used as a criterion to distinguish between these two low-grade B-cell lymphoproliferative processes. CD23 immunoreactivity was observed in 21 of 22 cases (95%) of SLL/CLL, whereas only 2 of 15 cases (13%) of MCL were reactive for this antigen; therefore, lack of CD23 reactivity is statistically significantly associated with MCL (P < 0.0001). In addition, lack of CD23 immunoreactivity is also statistically significantly associated with SLL with plasmacytoid differentiation in comparison with typical SLL (P < 0.0003), although only a small number of cases were evaluated. SLL/CLL, MCL, and SLL with plasmacytoid differentiation cases were all uniformly immunoreactive for pan-B-cell antigens such as CD20 and CD22. Immunoreactivity for CD23 appears to be a useful marker to aid in distinguishing SLL/CLL from MCL and may be helpful in routine immunophenotypic screening of low-grade B-cell derived lymphoproliferative processes.