CD20, high-affinity IgE receptor beta chain (FcepsilonRIbeta), and HTm4 are structurally related cell-surface proteins expressed by hematopoietic cells. In the current study, 16 novel human and mouse genes that encode new members of this nascent protein family were identified. All family members had at least four potential membrane-spanning domains, with N- and C-terminal cytoplasmic domains. This family was therefore named the membrane-spanning 4A gene family, with at least 12 subgroups (MS4A1 through MS4A12) currently representing at least 21 distinct human and mouse proteins. Each family member had unique patterns of expression among hematopoietic cells and nonlymphoid tissues. Four of the 6 human MS4A genes identified in this study mapped to chromosome 11q12-q13.1 along with CD20, FcepsilonRIbeta, and HTm4. Thus, like CD20 and FcepsilonRIbeta, the other MS4A family members are likely to be components of oligomeric cell surface complexes that serve diverse signal transduction functions.