Five cases of clinically aggressive, keratin-positive malignant lymphomas of B-cell type with unusual immunophenotypes were studied. All cases were extranodal: two from the stomach, one from soft tissue, one from the skin, and one from the spleen. These tumors were undifferentiated large-cell neoplasms that showed reactivity for low-molecular-weight keratin 8, but they were negative for keratin 19; three cases were also positive for epithelial membrane antigen. The immunohistochemical diagnosis was complicated by the fact that two of these cases lacked reactivity for leukocyte common antigen and three were CD20 negative. These findings simulated the immunophenotype of a carcinoma and led to an initial misdiagnosis of carcinoma. Although only two cases showed immunohistochemical evidence of B-cell lineage (CD20+), all five cases were documented as B-cell lymphomas on the basis of the clonal immunoglobulin heavychain gene rearrangement, as demonstrated by polymerase chain reaction (PCR) in all the cases and by Southern blot hybridization in three cases; all cases were negative for T-cell markers, and three cases showed germline configuration for T-cell receptor beta-chain. One case was strongly CD30 positive and represented large-cell anaplastic lymphoma of B-cell type. Our results show that some B-cell lymphomas can have unusual and confusing immunophenotypes, including keratin positivity and leukocyte antigen negativity. Use of PCR-based molecular genetic demonstration of clonal immunoglobulin heavychain gene rearrangement is helpful in establishing the correct diagnosis in such cases.