Objective. To investigate the possible association of the Fcγ receptor IIb (FcγRIIb) Ile/Thr187 transmembrane domain polymorphism, which significantly affects receptor signaling, with susceptibility to systemic lupus erythematosus (SLE) in Taiwanese patients. Methods. We used matrix-assisted laser desorption ionization-time-of-flight mass spectrometry to genotype 351 Taiwanese SLE patients and 372 age- and sex-matched healthy individuals from the same geographic area. Allele frequencies and genotype distributions were compared between the patients and controls, both as an aggregate and as stratified by sex, autoantibody profile, and clinical parameters. A combined analysis was conducted to assess the FCGR2B Thr187 allele as a common risk factor in different ethnic populations. Results. The minor Thr187 allele was significantly associated with SLE in Taiwanese subjects (P = 0.017, odds ratio [OR] 1.989 [95% confidence interval (95% CI) 1.119-3.553]). Interestingly, male SLE patients showed enrichment of the Thr/Thr187 genotype (24%; 7 of 29) as compared with female SLE patients (10%; 32 of 322) (P = 0.043, OR 2.884 [95% CI 1.028-7.839]). Additionally, SLE patients with Thr/Thr187 and He/Thr187 genotypes were more likely to have pleural effusions (P = 0.038, OR 1.874 [95% CI 1.033-3.411]) and anti-SSA/Ro antibody production (P = 0.046, OR 2.221 [95% CI 1.013-4.897]). Combined analysis of 4 groups of Asian patients strongly supported the association of the FCGR2B Thr187 allele with the lupus phenotype (P = 0.000159). Conclusion. The FcγRIIb transmembrane polymorphism is a strong disease susceptibility candidate in epistasis with other genetic effects in Taiwanese and other Asian populations. It may also play a more prominent role in male patients with SLE.