The aim of this study was to determine whether the functional protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism (rs2476601) confers susceptibility to systemic lupus erythematosus (SLE) in ethnically different populations. A meta-analysis was conducted on the PTPN22 C1858T polymorphism across 11 comparative studies. Meta-analysis showed an association between the PTPN22 1858T allele and SLE in all study subjects (odds ratio (OR) 1.560, 95% confidence interval (CI) 1.336, 1.822, p = 2.0 × 10(-8)). Analysis after stratification by ethnicity indicated that the PTPN22 1858T allele was significantly associated with SLE in Europeans and Hispanics (OR 1.490, 95% CI 1.280, 1.735, p = 2.0 ×10(-8); OR 2.355, 95% CI 1.644, 3.373, p = 2.9 × 10(-6)). The meta-analysis showed that the C/T + T/T genotype was associated with susceptibility to SLE in all study subjects, Europeans, and Hispanics populations, and an association between the T/T genotype with SLE in Europeans. African Americans had a much lower prevalence of the T allele (2.2%) than any other population studied, and Europeans had the highest frequency (9.5%). In conclusion, this meta-analysis confirms that the PTPN22 C1858T polymorphism is associated with SLE susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.