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Introduction Hepatitis C virus (HCV), a major cause of chronic liver disease, shows decreasing prevalence in Korea, yet regional disparities persist. This study aimed to examine the impact and temporal changes in individual characteristics and regional health inequalities on HCV infection to provide a framework for HCV elimination and management.Methods This nationwide population-based multilevel case–control study analysed 252 993 patients with HCV and 4 000 000 controls using National Health Insurance Service (NHIS) and population census data from 2005, 2010, 2015 and 2020. The Area Deprivation Index (ADI) was calculated for each area (region/town) using population census data. Sex-standardised and age-standardised HCV prevalences were estimated for each area using NHIS data. The association between area-level HCV and ADI was examined using correlation and linear regression analyses. Individual-level and area-level HCV infection risks were estimated using logistic regression and multilevel logistic regression models incorporating sex, age, HCV prevalence and ADI.Results The HCV prevalence (per 100 000) decreased from 151 to 117 (2005–2020). The maximum inter-area ADI gap decreased modestly (34.64 to 32.50). Although the correlation between ADI and HCV prevalence was weak across all areas, it was markedly stronger in high-prevalence areas (≥200/100 000). In logistic regression, residents of the most deprived areas had elevated risks vs the least deprived (2020 adjusted OR 1.37). Multilevel models showed age (individual level) and area HCV prevalence (area level) were dominant determinants. Deprivation increased an individual’s odds of HCV case status in ADI-only models; however, this association was not statistically significant after adjusting for area-level HCV prevalence and individual factors.Conclusions Effective HCV elimination requires tailored screening and treatment strategies that prioritise socioeconomically vulnerable areas among the high-prevalence areas.