ABSTRACT Background and Aims Glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) are widely used as first‐line direct‐acting antiviral (DAA) regimens for chronic hepatitis C, achieving high virus eradication rates. However, a small proportion of patients experience treatment failure, and the optimal retreatment strategies for such cases remain unclear. This nationwide, multicenter, prospective study aimed to evaluate the efficacy of retreatment regimens in patients who failed initial DAA therapy. Methods A total of 330 patients were enrolled, including 117 with prior GLE/PIB failure and 213 with prior SOF/LDV failure. The primary outcome was sustained virologic response at 12 weeks after retreatment (SVR12). Retreatment regimens included 12 weeks of GLE/PIB, sofosbuvir/velpatasvir (SOF/VEL) plus ribavirin (RBV), or SOF/LDV. Results Among patients retreated after GLE/PIB failure, SVR12 rates were 99.0% (98/99) with SOF/VEL + RBV, 92.3% (12/13) with GLE/PIB 12 weeks, and 100% (5/5) with SOF/LDV, with no significant differences among regimens. Among patients retreated after SOF/LDV failure, SVR12 rates were 100% (12/12) with SOF/VEL + RBV, 99.5% (197/198) with GLE/PIB 12 weeks, and 66.7% (2/3) with SOF/LDV. Retreatment of SOF/VEL + RBV or GLE/PIB demonstrated high therapeutic efficacy in patients with prior SOF/LDV failure. One patient who relapsed after GLE/PIB 8‐week therapy and harbored a P32del mutation achieved SVR12 with SOF/VEL + RBV retreatment. Conclusions Retreatment with SOF/VEL + RBV, GLE/PIB for 12 weeks, or SOF/LDV achieved high SVR12 rates, indicating that effective viral eradication is feasible using currently available DAA regimens even after prior treatment failure.