The diagnosis of B-cell chronic lymphoproliferative disorders is a great challenge when made in a background of polyclonal B cells. We studied the diagnostic usefulness of aberrant CD22 expression for differentiating neoplastic from benign B cells by 4-color flow cytometry. Of 56 cases of B-cell chronic lymphoproliferative disorders, we found that neoplastic cells showed aberrant CD22 expression in 39 (70%) of 56 cases, including chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, hairy cell leukemia, and follicular lymphoma. In 4 cases, monoclonality was detected definitively only by evaluating the immunoglobulin light chain restriction in B cells with aberrant CD22 expression because numerous polyclonal B cells were present. Aberrant CD22 expression is a useful marker for detection of monoclonal B cells admixed with numerous benign polyclonal B cells.