Objective. To investigate the association of the functional FCRL3 single-nucleotide polymorphism (SNP) -169T/C with disease phenotypes and susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Taiwanese. Methods. FCRL3 SNP -169T/C was genotyped in 573 patients with SLE, 670 patients with RA, and 758 controls. Genotype distributions and allele frequencies were compared among the 3 groups as aggregates or as stratified by clinical characteristics, autoantibody profile, and sex within patient groups. Results. Overall, FCRL3 SNP -169T/C was not associated with susceptibility to either SLE or RA. However, -169CC genotype was significantly reduced in leukopenia-positive SLE patients as compared to the leukopenia-negative SLE patients (CC vs CT+TT, p = 6 × 10-4, OR 0.444, 95% CI 0.279-0.708) and controls (p = 6.1 × 10-3, OR 0.583, 95% CI 0.396-0.857). On the other hand, -169TT genotypes were significantly more numerous in RA patients with non-destructive disease as compared with patients with destructive disease (CC+CT vs TT: p = 0.007, OR 1.672, 95% CI 1.149-2.432). The -169T allele frequency was also significantly increased in non-destructive RA compared with patients with destructive disease (C vs T: p = 0.010, OR 1.423, 95% CI 1.089-1.859). FCRL3 SNP -169TT homozygous donors were significantly more numerous among female cyclic citrullinated peptide (CCP)-negative RA patients versus female CCP-positive RA patients (CC+CT vs TT: p = 0.019, OR 1.64, 95% CI 1.085-2.479). Conclusion. The functional FCRL3 SNP -169T/C appears to play important roles in the development of certain phenotypes such as SLE leukopenia and RA disease severity in Taiwanese patients with SLE and RA. The Journal of Rheumatology Copyright © 2011. All rights reserved.