c-Maf, a leucine zipper-containing transcription factor, is involved in the t(14;16)(q32;q23) translocation found in 5% of myelomas. A causal role for c-Maf in myeloma pathogenesis has been proposed, but data on c-Maf protein expression are lacking. We therefore studied the expression of c-Maf protein by immunohistochemical analysis in myelomas and in a wide variety of hematopoietic tissue. c-Maf protein was detected in a small minority (4.3%) of myelomas, including a t(14;16)(q32;q22-23)/IgH-Maf+ case, suggesting that c-Maf protein is not expressed in the absence of c-Maf rearrangement. In contrast, c-Maf was strongly expressed in hairy cell leukemia (4/4) and in a significant proportion of T-cell (24/42 [57%]) and NK/T-cell (49/97 [51%]) lymphomas, which is in keeping with prior gene expression profiling and transgenic mouse studies. Up-regulation of c-Maf protein occurs in a small subset of myelomas, in hairy cell leukemia, and in T- and NK-cell neoplasms. Its detection may be of particular value in the differential diagnosis of small cell lymphomas.