The role of hepatitis C virus (HCV) in insulin resistance (IR) is not fully understood. The aim of this study was to determine the impact of amino acid (aa) substitutions in the core region of HCV according to IR and to identify clinical and laboratory associations. Ninety-two treatment-naive HCV patients were recruited to determine laboratory data and blood cell count. IR was determined using Homeostasis Model Assessment (HOMA) index where IR was defined as HOMA ≥2. HCV RNA load and genotype were determined by Abbott Real time HCV. HCV core region was determined by direct nucleotide sequencing. Bivariate analysis was conducted using HOMA IR ≥2 as a dependent factor. IR prevalence was 43.5% (n = 40), vitamin D sufficiency was found in 76.1% (n = 70) and 72.8% (n = 67) had advanced liver fibrosis. In the bivariate analyses, elevated values of γGT (p = 0.024) and fibrosis staging (p = 0.004) were associated with IR, but IR was not related to core mutations. The presence of glutamine in position 70 was associated with low vitamin D concentration (p = 0.005). In the multivariate analysis, no variable was independently associated with HOMA-IR. In conclusion, lack of association between IR and HCV core mutations in positions 70 and 91 suggests that genetic variability of this region has little impact on IR.