The determinants of hepatitis C virus (HCV) viral load remain incompletely understood and may differ in females, who are relatively protected from the consequences of HCV infection during their reproductive years. We aimed to evaluate how age affects the relationship between sex and viral load. n = 922 patients (males n = 497, median age 62 years), all naïve to direct antiviral agents, were studied. Females were older (median age 68 vs. 57, p < 0.001) and had a higher prevalence of genotype 2 (33% vs. 20%, p < 0.001) than males; there was no difference between sexes regarding the METAVIR stage. The median HCV RNA concentration was 1.017 × 10⁶ IU/mL (interquartile range, 0.286–2.400). Among males, the METAVIR stage was the strongest independent predictor of a high viral load (defined as the highest two quartiles), with advanced stages inversely associated with viral load (p = 0.008). In females, age was the only independent predictor, with women aged ≥55 years exhibiting higher loads (p = 0.009). These findings are consistent with data showing that estrogens exert an antiviral effect in in vitro models of HCV. Their declining levels after the menopause may explain the “catch-up” phase of HCV-related liver disease, observed in older women.