To evaluate the value of morphologic, immunohistochemical and molecular analyses, we studied 21 skin biopsy specimens from 19 patients with primary cutaneous B-cell infiltrates. Morphologic review by two independent dermatopathologists confirmed the consensus diagnoses of lymphoma (n = 6) or benign lymphoid hyperplasia (n = 6). A discordant diagnosis was made for the other samples (n = 9), which were thereafter considered as unclassified lymphoid infiltrates. Immunohistochemical analysis showed either a monotypic expression of immunoglobulin light chain or a positive staining with anti-bcl-2 antibodies in three and four samples, respectively, of lymphoma. Polymerase chain reaction was used to analyze immunoglobulin heavy chain and T-cell receptor gamma chain gene rearrangement and to amplify t(14;18) and t(11;14) break points. A clonal molecular marker was detected in 12 of 19 patients. Among these 12 patients, a final diagnosis of lymphoma was confirmed in 8 patients, including the 6 with a morphologic diagnosis of lymphoma. Two patients with clonal benign lymphoid hyperplasia and two with clonal unclassified lymphoid infiltrate presented a benign clinical outcome; one patient was lost to follow-up. Alternatively, no clonal molecular marker was found in two of the patients with lymphoma. The morphologic and molecular criteria, therefore, provided complementary and partially overlapping information for the diagnosis of cutaneous B-cell infiltrates. We proposed a practical use for these data.