International Normalized Ratio (INR), which standardizes prothrombin time (PT) during oral anticoagulation, has been extended to standardize PT in liver diseases and is included in all prognostic models of survival, the classification of CHILD-Pugh or Meld. However, the mechanisms of PT prolongation in liver diseases differ from those involved in oral anticoagulation. Our aim was to assess the validity of the INR system for patients with liver disease associated with viral hepatitis. We prospectively collected blood samples from 61 patients with liver disease associated with viral hepatitis; control patients were on warfarin (n = 20). PTs were measured on a STA-R coagulometer with six thromboplastin reagents, and INRs were calculated using instrument-specific ISIs. Simultaneously, we selected 15 pairs of patients in the study population and in the control population such that INR values for each patient pair are almost equal. For these 15 pairs of patients, we performed factor assays and measured the coagulant activities of factors II, V, VI, and X and fibrinogen. Analysis of results for the control population confirms the validity of the INR system for patients on oral anticoagulants in that there was no significant difference between the reported INRs for the six different thromboplastin reagents. Conversely, for the study population, there was a significant difference between the INR results using the different reagents. Results for fibrinogen and factors V, VII, and X showed significant differences between the two groups; however, control and patient results for factor II were not statistically different. The INR system is not valid for comparison of patients with liver disease associated with viral hepatitis because different reagents do not yield the same INR for the same sample.