We recently showed in a proof-of-concept study that real-time modeling-based response-guided therapy (RGT) can shorten hepatitis C virus (HCV) treatment duration with sofosbuvir/velpatasvir, elbasvir/grazoprevir and sofosbuvir/ledipasvir without compromising efficacy, confirming our retrospective modeling reports in more than 200 patients. However, retrospective modeling under pibrentasvir/glecaprevir (P/G) has yet to be evaluated. In the current study modeling HCV kinetics in 44 cirrhotic and non-cirrhotic patients predicts that P/G treatment might have been reduced to 4, 6 and 7 weeks in 16%, 34% and 14% of patients, respectively. These results support the further evaluation of a modeling-based RGT approach under P/G therapy.