Several linkage analyses have consistently shown that systemic lupus erythematosus (SLE) susceptible genes are located on chromosome 1q21-44. In this study, two major candidate genes, interleukin-10 (IL-10) and Fc gamma receptor IIa (FcγRIIa), within these regions were investigated in Thai SLE patients. The genotyping of three single-nucleotide polymorphisms (promoter area: -1082, -819 and -592) within IL-10 gene and one polymorphism (change amino acid at position 131) within FcγRIIa gene was determined in 195 SLE patients and 159 ethnically matched controls. The RR/RH genotypes of FcγRIIa were found to be significantly increased in SLE patients compared with healthy controls [OR = 2.01, 95% confidence interval (CI) = 1.28-3.14, P = 0.001]. Interestingly, the synergistic effect between RR/RH genotypes of FcγRIIa and ACC/ACC haplotype of IL-10 in susceptibility to SLE was observed (OR = 7.84, 95% CI = 1.60-52.04, P = 0.002). In addition, the FcγRIIa, RR homozygotes was also strongly associated with anticardiolipin antibody production (OR = 6.09, 95% CI = 1.38-30.54, P = 0.006). The result demonstrated that ACC haplotype of IL-10 gene and FcγRIIa R131 polymorphism can be used as marker for genetic susceptibility and severity to SLE in Thai population, particularly individuals carrying both specific genotypes.