BACKGROUND Posttransplant B-cell lymphoproliferative disorders (PTLDs) constitute a heterogeneous group that includes hyperplastic and unique polymorphic lesions at one end of the spectrum and monomorphic lymphoid proliferations indistinguishable morphologically from conventional B-cell non-Hodgkin lymphomas (NHLs) at the other end. Almost all the PTLDs are of B-cell origin, with only rare examples of T-cell phenotype described. Despite a plethora of information available on the morphologic spectrum, pathogenetic role of Epstein-Barr virus, and various treatment options, a detailed flow cytometric immunophenotypic evaluation of PTLDs is largely lacking. OBJECTIVE To evaluate the immunophenotypic profiles of various PTLDs using multiparameter flow cytometric analysis to compare and contrast with conventional de novo B-cell lymphoproliferative disorders and to identify any immunophenotypic patterns useful in diagnosis. METHODS We retrospectively analyzed data on the immunophenotype of 25 cases of pediatric and adult PTLD (12 cases of monomorphic PTLD [m-PTLD] and 13 cases of polymorphic PTLD [p-PTLD]) using multiparameter flow cytometry in addition to routine morphologic and immunohistochemical evaluation. The flow cytometric immunophenotypic data were also compared and contrasted with 334 cases of various de novo B-cell NHLs during the same period as a control group. RESULTS We observed a much higher incidence of lack of surface immunoglobulin light chains and CD20 expression in B-cell PTLDs using multiparameter flow cytometry in comparison with de novo B-cell NHL as a group (with the exception of small lymphocytic lymphoma). Four (16%) of 25 cases of PTLD (3 m-PTLD and 1 p-PTLD) showed almost complete lack (CD20%/CD19% ratio < 1:9) of CD20 expression in contrast to only 8 ( approximately 2%) of 334 cases of de novo B-cell NHL (P =.007). Several other cases of both m-PTLD and p-PTLD also showed partial and dim expression of CD20. Nine (36%) of 25 cases, including 5 cases of m-PTLD and 4 of p-PTLD, showed either an almost complete lack (light chains%/CD19% ratio < 1:9) or significant loss (>50% loss) of surface immunoglobulin light chains in contrast to less than 5% incidence of light-chain negativity in conventional de novo B-cell NHL. Immunoglobulin light-chain clonality was observed in 9 cases (5 m-PTLD and 4 p-PTLD). Seven cases (5 p-PTLD and 2 m-PTLD) had polyclonal expression of immunoglobulin kappa and lambda light chains. The m-PTLD showed expression patterns of CD5, CD10, and CD23 similar to their de novo counterparts. CONCLUSIONS Both polymorphic and monomorphic PTLDs show a higher incidence of lack of CD20 and surface immunoglobulin light-chain expression. The lack of CD20 expression in these lesions may have therapeutic implications, since anti-CD20 antibody has increasingly become an important modality in the treatment of B-cell lymphoproliferative disorders, including posttransplant disorders.