BACKGROUND: The protein tyrosine phosphatase non receptor type 22 (PTPN22) gene inhibits T-cell activation. A functional single nucleotide polymorphism (SNP) Arg620Trp (rs2476601), resulting from a C→T substitution at nucleotide position 1858, is a significant risk factor for rheumatoid arthritis (RA) in European populations. The variant allele results in a gain of function that alters the threshold for T-cell signalling and abnormal T regulatory cell function. AIM: To investigate the role of the PTPN22 R620W polymorphism in disease susceptibility and severity in Black South Africans (BSA) with RA. METHODS: A cohort of 187 BSA patients with RA and 93 ethnically matched Black and 60 White controls with no history of RA or other autoimmune diseases were studied. Genotyping was performed by the polymerase chain reaction and pyrosequencing. RESULTS: The rs2476601 SNP was nonpolymorphic in both Black patients and Black control subjects with total absence of the variant ‘T’ allele. In White control subjects the frequency of the ‘T’ allele was 0.092, with T/T, C/T and C/C genotype frequencies of 0.00, 0.183, and 0.817, respectively. CONCLUSION: This study shows that the rs2476601 SNP of the PTPN22 gene is nonpolymorphic in BSA and therefore not associated with RA but the minor ‘T’ allele frequency in White South Africans is similar to that in other European populations. However, since variations in the rest of the gene were not investigated, these results do not exclude other PTPN22 polymorphisms from playing a role in RA susceptibility in BSA.