Background Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment. Methods In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed. Results Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naïve patients ( p  = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p  = 2.68 × 10 –5 ; genotype 2 vs. 3, p  = 3.28 × 10 –5 ) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1–3 (99.1% 1209/1220) and chronic kidney disease (CKD) stage 4–5 (98.9% 188/190) patients, or between cirrhotic (99.0% 398/402) and non-cirrhotic (99.1% 999/1008) patients. Multiple logistic regression analysis revealed that genotype 3 OR 33.404, 95% CI (7.512–148.550), p value ( p  = 4.06 × 10 –5 ) and past experience of IFN-free DAAs OR 3.977, 95% CI (1.153–13.725), p value ( p  = 0.029) were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4–5 (41.6% 79/190) than CKD stage 1–3 (26.1% 319/1220) patients ( p  = 2.00 × 10 –5 ). AEs were also significantly higher in cirrhotic (38.6% 155/402) than in non-cirrhotic (24.1% 243/1008) ( p  = 2.91 × 10 –18 ) patients. Conclusions G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.