Here, we report the identification of Fc receptor homolog expressed in B cells (FREB), a unique B cell-specific molecule that is distantly related to FcgammaRI (receptor I for the Fc fragment of IgG) and is encoded on human chromosome 1q, within the FcgammaR gene region. FREB has an intracellular distribution and lacks a canonical transmembrane domain. In addition, FREB lacks bona fide Fc fragment binding regions and does not bind immunoglobulins. By using specific monoclonal antibodies, we show that FREB is preferentially expressed in germinal center centroblasts, which undergo affinity maturation and class-switch recombination. Together, these characteristics indicate that FREB may have a unique role in B cell differentiation. FREB is also expressed in some B cell lymphomas, most of which have centroblast origin. Remarkably, FREB is expressed in a subset of diffuse large B cell lymphomas, providing a unique marker for the characterization of this B cell malignancy.