The identification of hepatitis C virus (HCV) virus-human protein interactions will not only help us understand the molecular mechanisms of related diseases but also be conductive to discovering new drug targets. An increasing number of clinically and experimentally validated interactions between HCV and human proteins have been documented in public databases, facilitating studies based on computational methods. In this study, we proposed a new computational approach, rotation forest position-specific scoring matrix (RF-PSSM), to predict the interactions among HCV and human proteins. In particular, PSSM was used to characterize each protein, two-dimensional principal component analysis (2DPCA) was then adopted for feature extraction of PSSM. Finally, rotation forest (RF) was used to implement classification. The results of various ablation experiments show that on independent datasets, the accuracy and area under curve (AUC) value of RF-PSSM can reach 93.74 %