Background: Screening for esophageal varices (EVs) in patients with chronic liver disease is critical for identifying those needing primary prophylaxis against variceal bleeding. The gold standard for EV screening is endoscopy, an invasive and costly procedure often avoided by patients. This necessitates the need for non-invasive predictive tools for the presence of EVs and high-risk varices (HRVs). The P²MS index, a relatively new model, has shown promise in this regard. Objective: This study aimed to evaluate the effectiveness of the P²MS index, alongside APRI and FIB-4 scores, in predicting the presence of EVs and HRVs in patients with hepatitis C-related chronic liver disease. Methods: Conducted at the Sindh Institute of Urology and Transplantation's Hepato-Gastroenterology department, this cross-sectional study involved 375 participants aged 18-50 years, recently diagnosed with liver cirrhosis due to hepatitis C. Excluding those with varied medical backgrounds, the study used non-probability consecutive sampling. Diagnostic procedures included esophagogastroduodenoscopy (EGD) and complete blood count. P²MS index, APRI, and FIB-4 scores were calculated for each participant. Data analysis was performed using SPSS version 25.0, focusing on the Area Under the Receiver Operating Curve (AUROC) to assess diagnostic accuracy. Results: In our population, the P²MS index at a cutoff of <10.7 showed a specificity of 93.22% and sensitivity of 87.88% for predicting the presence of EVs, with a PPV and diagnostic accuracy exceeding 90%. For HRVs, a cutoff of <5.4 demonstrated an excellent NPV, alongside good sensitivity, specificity, and diagnostic accuracy. Compared to APRI and FIB-4, the P²MS index had the highest AUROC for predicting the presence of EVs (0.92, 95% CI 0.89-0.95, p<0.001). For HRVs, it was comparable to APRI (AUROC=0.88, 95% CI 0.85-0.92, p<0.01) and superior to FIB-4. Conclusion: The P²MS index is an effective non-invasive tool for screening EVs in patients with hepatitis C-related chronic liver disease, demonstrating high accuracy for predicting the presence of EVs. However, its efficacy in predicting HRVs is comparable to other non-invasive indices and warrants further validation.