This study explored the utility of CD38 immunodetection in paraffin-embedded tissue sections for differentiating follicular lymphoma (FL) from reactive follicular hyperplasia (RFH) by examining RFH (n = 47) and FL (n = 178). In RFH specimens, uniform weak-to-moderate CD38 immunostaining was observed in centrocytes and centroblasts across germinal centers (GCs). Moreover, these specimens contained a subset of strongly CD38-positive cells predominantly located in the light zone, which may represent antigen-selected surviving centrocytes that are committed to differentiate into plasma cells, i.e., centrocytoid plasma cells (CPCs). In FL specimens, CD38 staining yielded two patterns. In pattern I (146 specimens), weak-to-moderate CD38 staining was observed in tumor cells within neoplastic follicles. Neoplastic follicles in 126 of the 146 specimens did not contain strongly CD38-positive CPCs. Furthermore, individual neoplastic follicles in the remaining 20 FL specimens contained very few strongly CD38-positive cells (which may represent normal residual CPCs). In pattern II (32 cases), neoplastic follicles exhibited loss of CD38 expression accompanied by disappearance of CPCs. In conclusion, compared with RFH, the decrease of strongly CD38-positive CPCs in neoplastic follicles was a striking alteration, reflecting blocks in the lymphoid differentiation pathway. Moreover, loss of CD38 expression in neoplastic GC B-cells in some FL specimens can serve as an immunophenotypic characteristic of FL.