To elucidate the genotype-specific virus-host-drug interaction and the on-treatment viral kinetics in predicting sustained virologic response (SVR), serial serum hepatitis C virus (HCV) ribonucleic acid (RNA) levels at baseline, treatment week 2 (W2), treatment week 4 (W4), and treatment week 12 (W12) were measured in 199 chronic HCV-infected Taiwanese patients receiving interferon-alpha (INF-alpha) 6 million units (MU) three times weekly plus 1000 to 1200 mg/day of ribavirin for 24 weeks. The SVR rate was 90.5% (95/105) for HCV genotype 2 (HCV-2) patients and 47.9% (45/94) for HCV-1 patients (P < 0.0001). HCV-2 patients had a significantly higher rate of rapid virologic response (RVR) at W2 than HCV-1 patients. HCV RNA negativity at W4 had the highest accuracy of prediction (80%) of SVR with sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 81%, 79%, 78%, and 82%, respectively, for HCV-1 patients. HCV RNA negativity or 2 logs drop at W4 had the highest accuracy of prediction (92%) with sensitivity, specificity, PPV, and NPV of 100%, 20%, 92%, and 100%, respectively, for HCV-2 patients. In multivariate analysis, the significant factors associated with SVR in HCV-1 patients were HCV RNA negativity at W12 and W4. HCV RNA negativity or 2 logs drop was the only significant factor associated with SVR in HCV-2 patients. In conclusion, a RVR at W4 could predict an SVR with a high degree of accuracy to a 24-week course of high-dose IFN/ribavirin for both HCV-1 patients and HCV-2 patients. With respect to each HCV genotype, the on-treatment virologic responses are the most important factors associated with SVR.