Objective. The low-affinity receptor Fcγ receptor IIb (FcγRIIb), with an immunoreceptor tyrosine-based inhibitory motif (ITIM) in the cytoplasmic domain, down-regulates humoral immune responses and modulates the risk of autoimmunity in animal models. The transmembrane domain of FcγRIIb may also contribute to receptor signaling. Therefore, we investigated the biologic significance of single-nucleotide polymorphisms (SNPs) throughout the coding region. Methods. Discovery of SNPs in FCGR2B was performed by direct cycle sequencing of complementary DNA samples derived by reverse transcriptase-polymerase chain reaction. To assess the biologic significance of the nonsynonymous transmembrane SNP, we studied 3 functions influenced by the FcγRIIb transmembrane domain: tyrosine dephosphorylation of CD19, inhibition of B cell receptor (BCR)-induced calcium response, and modulation of BCR- or anti-Fas-induced apoptosis. Results. The nonsynonymous C-to-T transition in the first cytoplasmic exon, originally reported in the Raji cell line, was not found in either the African-American or the Caucasian population, but a nonsynonymous T-to-C transition at nucleotide 775 in exon 4 of FCGR2B, which changes isoleucine to threonine at residue 187 in the transmembrane domain, was significantly more common in African Americans. Using the FcγRIIb mouse B cell line IIA1.6, we expressed both allelic forms as both full-length and truncated cytoplasmic domain constructs. The FCGR2B-187T allele mediated a higher level of CD19 dephosphorylation (P = 0.029) and a greater degree of inhibition of the calcium response (P = 0.003) when co-engaged with BCR than did FCGR2B-1871, independent of the presence of the ITIM. In contrast, FcγRIIb modulation of BCR-induced and anti-Fas antibody-induced cell death rates were similar in IIA1.6 cells expressing either the 1871 or the 187T allelic form. Conclusion. The differential activity of FCGR2B alleles suggests a novel mechanism of FcγRIIb regulation that may influence the risk of autoimmune disease.