With the introduction of direct-acting antivirals (DAAs), treatment against hepatitis C virus (HCV) has significantly improved. To manage and control this worldwide infectious disease better, the "best" multidrug treatment is demanded based on scientific evidence. However, there is no method available that systematically quantifies and compares the antiviral efficacy and drug-resistance profiles of drug combinations. Based on experimental anti-HCV profiles in a cell culture system, we quantified the instantaneous inhibitory potential (IIP), which is the logarithm of the reduction in viral replication events, for both single drugs and multiple-drug combinations. From the calculated IIP of 15 anti-HCV drugs from different classes [telaprevir, danoprevir, asunaprevir, simeprevir, sofosbuvir (SOF), VX-222, dasabuvir, nesbuvir, tegobuvir, daclatasvir, ledipasvir, IFN-α, IFN-λ1, cyclosporin A, and SCY-635], we found that the nucleoside polymerase inhibitor SOF had one of the largest potentials to inhibit viral replication events. We also compared intrinsic antiviral activities of a panel of drug combinations. Our quantification analysis clearly indicated an advantage of triple-DAA treatments over double-DAA treatments, with triple-DAA treatments showing enhanced antiviral activity and a significantly lower probability for drug resistance to emerge at clinically relevant drug concentrations. Our framework provides quantitative information to consider in designing multidrug strategies before costly clinical trials.instantaneous inhibitory potential H epatitis C virus (HCV) affects ∼170 million people worldwide (1-4) and is a major cause of liver cirrhosis and hepatocellular carcinoma. The standard treatment has long been a combination of IFN, IFN-α or pegylated IFN-α (peg-IFN-α), with ribavirin (RBV), with a sustained virological response (SVR) rate of around 50% (5). Improvements in the SVR rate have been made by using anti-HCV agents that inhibit viral-derived factors or cellular factors that are essential for viral replication. Agents inhibiting viral proteins, called direct-acting antivirals (DAAs), typically target HCV nonstructural (NS)3 protease, NS5A, and NS5B polymerase (3). Anti-HCV molecules that target cellular factors, so-called hosttargeting antivirals (HTAs), include those HTAs inhibiting cyclophilins and microRNA-122, which are required for HCV replication (3). These agents have been evaluated in clinical trials. In 2011, the protease inhibitors (PIs) telaprevir (TPV) and boceprevir were approved by the US Food and Drug Administration for use in combination with peg-IFN and RBV. These drug combinations achieved significantly improved clinical outcomes, attaining more than a 70% SVR rate (5).