Degenerative osteoarthritis (OA) is the most common joint disease. However, its etiology has not been clearly understood. We aimed to investigate the association between the IL-6-174G/C gene variant responsible for regulating IL-6 functions and primary knee osteoarthritis (PKOA). Patients older than 40 years who presented between February 2012 and April 2013 and were diagnosed with PKOA and had grade 3 (i.e., moderate) or 4 (i.e., severe) disease constituted the case group. Healthy volunteers formed the control group. Genomic DNA was extracted from blood leukocytes in both case and control groups, and the IL6-174 G/C genotypes were determined. Two groups were compared regarding demographic, clinical, radiological findings, and IL-6-174 genotyping results. Both case and control groups included 90 patients each. No statistically significant difference was found between the two groups regarding gender distribution, patient age, and body weight. The frequency of the mutant base pairs GC and CC in the IL-6-174 promoter region were significantly higher in controls than in cases. Women with genotypes including C alleles were genetically protect ed against the clinical disease. Similar findings were not detected in the male patient group. The IL6-174 G/C gene polymorphism does not increase the risk of PKOA. However, the mutant C allele can be protective against PKOA in female patients. Studies conducted on larger patient populations from different ethnic backgrounds are needed to confirm our findings since our sample size is relatively small.