The hepatitis C virus (HCV) has infected at least 4 million people in the United States, and is one of the leading causes of liver cirrhosis, end–stage liver disease and hepatocellular carcinoma. HCV genotype 1 is responsible for the majority of HCV infections in the U.S. and is highly resistant to anti–HCV therapy. The current standard of care for treating HCV is a pegylated interferon alpha (PEGIFN) 2a or 2b combined with ribavirin (RBV). African American (AA) patients have lower rates of sustained virologic response (SVR) to combination therapy compared to Caucasians (CA) in part due to a higher incidence of HCV genotype 1. However, other mechanisms of impaired viral response in AA are yet to be identified. In a previous study, no racial difference was found in the pharmacokinetics (PK) of PEGIFN. Thus, it is possible that RBV PK may be altered in AA. Moreover, the anti–viral activity of RBV was shown to be concentration–dependent. Therefore we hypothesized that altered RBV PK is a significant factor contributing to impaired virologic response to PEGIFN combination therapy in AA and CA with HCV genotype 1. To test this hypothesis, we pursued 4 aims. First, a sensitive and specific method using high performance liquid chromatography with tandem mass spectrometry was established to quantify RBV plasma concentrations in human plasma. Next, a population PK model of RBV based on 144 patients enrolled in the VIRAHEP–C study evaluated the impact of race on RBV PK. A population pharmacodynamic (PD) model was then developed to identify host factors associated with SVR. Lastly, PK simulations were performed to develop novel high–dose regimens of RBV in AA. The results showed that body weight was a significant covariate for apparent clearance of RBV. Both body weight and race were significant covariates on apparent peripheral volume (Vp/F), with Vp/F nearly 50% greater in AA compared to CA. Insulin resistance, RBV exposure during the first week of therapy, and IL28B–related single nucleotide polymorphism (SNP) rs12979860 predicted SVR in the PD model. A series of high-dose RBV regimens were developed based on simulation data to maximize drug exposure and SVR. In conclusion, the results of this population PK/PD study strongly support future studies of alternative dosing strategies to optimize RBV exposure and SVR in AA following treatment with PEGIFN and RBV for HCV genotype 1.