We compared surface immunoglobulin heavy chain isotype expression with a number of laboratory, morphologic, and immunophenotypic features in a series of 76 cases of B-cell chronic lymphocytic leukemia (B-CLL). Fifty-five cases were IgM+/IgD+, a phenotype associated with antigenically naïve B cells; 16 cases expressed IgD without IgM, a phenotype seen in a subset of normal B cells with extensive somatic immunoglobulin variable region (IgV) gene mutations; and 5 cases were IgD-, a phenotype associated with memory B cells. WBC count, atypical morphologic features, atypical immunophenotypic characteristics, and CD38 expression were nonrandomly distributed among the 3 categories of heavy chain isotype expression. Moreover, a WBC count more than 30,000/microL (30 x 10(9)/L), atypical morphologic features, and CD38 expression in more than 30% of neoplastic cells (all adverse prognostic factors in B-CLL) were less common among IgD-only cases than among IgM+/IgD+ and IgD- cases. These data demonstrate that surface immunoglobulin heavy chain isotype expression is associated with several laboratory, morphologic, and immunophenotypic features in B-CLL. The subset of B-CLL with the IgD-only phenotype is associated with several favorable prognostic factors, suggesting the possibility that IgD-only B-CLL may be associated with a favorable prognosis.