Rheumatoid arthritis (RA) is a multifactorial disease that is increasing in incidence worldwide. It is associated with a complex mode of inheritance, with many genes being involved in the development and progression of the disease. Genome-wide association studies in different populations have recently revealed a significant association between a TRAF1/C5 and a STAT4 polymorphism and the development of RA. In the present study we performed a case-control study in the population of the island of Crete, Greece, aiming to replicate the former findings in a genetically homogeneous cohort of patients. We found that mutated allele A or genotypes A/A and G/A of the TRAF1/C5 rs10818488 SNP were more common in individuals with RA than in control individuals (odds ratio [OR]=1.7, 95% confidence interval [CI]=1.35-2.15, and OR=2.22, 95% CI=1.61-3.05, respectively). Similarly, mutated allele T or genotypes T/T and G/T of the STAT4 rs7574865 SNP were also associated with susceptibility to RA (OR=1.9, 95% CI=1.46-2.50, and OR=2.37, 95% CI 1.73-2.25, respectively). Thus, we conclude that mutant alleles or genotypes of both polymorphisms examined are associated with the development of RA in our population.