Abstract: The gene encoding signal transducer and activator of transcription 4 (STAT4) has been documented to be associated with rheumatoid arthritis (RA) in several populations. The aim of this study was to determine the association of the STAT4 gene polymorphism (rs7574865) with RA in the Iranian population. Methods: This study included 612 Iranian RA patients and 389 healthy control subjects. For all samples, DNA was genotyped for STAT4 G>T (rs7574865) polymorphism using the MGB TaqMan Allelic Discrimination method. Results: In our survey, the frequencies of GG, GT, and TT genotypes were 50%, 41.3%, and 8.7% in RA patients, and 51.4%, 37.5%, and 11.1% in controls (P > 0.05), respectively. STAT4 rs7574865 alleles were not associated with the disease risk in the Iranian population (P > 0.05). Conclusions: Although most studies have proposed STAT4 polymorphisms as a susceptible risk factor for RA, we did not detect any significant association between the STAT4 polymorphism and RA in our study. Population-based studies help to identify genetic determinants of disease susceptibility. Possible explanations for differences in susceptible genetic factors among populations could be different genetic predispositions and contribution of gene–gene or gene–environment interactions. # 2016 Indian Rheumatology Association. Published by Elsevier B.V. All rights reserved.