In this study, we aim to identify patient characteristics that predict severe thrombocytopenia induced by peginterferon alfa-2a in hepatitis C virus–infected patients. Demographic, clinical, and genetic data collected from patients with chronic hepatitis C virus infection (n = 232; age ≥18 years) who received peginterferon alfa-2a following eltrombopag treatment. Predictors of severe thrombocytopenia (platelet count below 50 GI/L) were identified using a 2-step approach: First, univariate analysis, using χ2 test for categorical variables and t test for continuous variables, was performed to identify possible predictors of severe thrombocytopenia (P < 0.05). Second, a logistic regression with backward stepwise selection was then performed using predictors identified in univariate analysis step to produce final model containing independent predictors at P < 0.05. Logistic model identified several predictors of severe thrombocytopenia. Increased spleen length and increased alkaline phosphatase levels increases the likelihood of severe thrombocytopenia. However, being Central/South Asian, increased neutrophils count and increased platelet baseline count decreases the probability of developing severe thrombocytopenia. In summary, we identified several patient characteristics that predict severe thrombocytopenia induced by peginterferon alfa-2a. Early selection of individuals with high risk of developing interferon-associated severe thrombocytopenia allows early intervention (such as eltrombopag treatment). Early intervention in turn minimizes the odds of developing severe thrombocytopenia and allows the continual of antiviral therapy before patient progress into liver decompensation.