Single nucleotide polymorphisms in pre‑microRNA (miRNA) may alter miRNA expression levels or processing and contribute to susceptibility in a wide range of diseases. The present study aimed to evaluate the possible association between rs2910164 and rs3746444 of the pre-miRNA (hsa-mir-146a and hsa-mir-499) polymorphisms and susceptibility to rheumatoid arthritis (RA) in an Iranian population. This case-control study was performed on 104 patients with RA and 110 healthy individuals. Tetra amplification refractory mutation system-polymerase chain reaction was used to genotype the hsa-mir-499 rs3746444 and hsa-mir-146a rs2910164 polymorphisms. The hsa-mir-499 rs3746444 polymorphism was a risk factor for predisposition to RA in codominant [TT vs. TC: odds ratio (OR), 2.11; 95% confidence interval (CI), 1.08-4.11; p=0.029; TT vs. CC: OR, 3.88; 95% CI, 1.68-8.98; p=0.002], dominant (TT vs.
Tc-cc: OR, 2.64; 95% CI, 1.48-4.72; p=0.001) and recessive (TC-CC vs. CC: OR, 3.05; 95% CI, 1.36-6.83; p=0.007) tested inheritance models. In addition, the rs3746444 C allele was a risk factor for RA (OR, 2.49; 95% CI, 1.63-3.81; p<0.0001). No significant difference was found between the groups concerning the rs2910164 polymorphism (χ2=0.348, p=0.841). Our findings demonstrated that the hsa-mir-499 rs3746444, but not mir-146a rs2910164, polymorphism is associated with an increased RA risk in a sample of the Iranian population. Larger studies with different ethnicities are required to validate our findings.