Introduction: The Baveno VI consensus recommended the use of noninvasive predictors to identify patients at high risk of esophageal varices (EV) in whom endoscopic evaluation is most needed. Kallistatin is a protein molecule synthesized by the liver, and its level declines with the deterioration of liver functions. We aim to explore the role of kallistatin as a predictor of esophageal varices. Methods: This case–control study included 70 cirrhotic patients (35 patients with EV and 35 patients without EV). The laboratory investigations and upper GI endoscopy were performed, and the serum kallistatin level was measured in all patients. Results: The mean level of serum kallistatin was significantly lower in patients with varices (12.2 ± 5.6 vs 16.9 ± 4.8 μg/ml, p = 0.009). It also shows a significant decline in patients with large varices. Kallistatin can predict the presence of EV and large EV at cut off values of 15.8 and 8.9 μg/ml, respectively, with sensitivity and specificity of 71.4% and 54.3% for EV and 50% and 94.8% for large EV. Discussion: Kallistatin is a promising marker that can be used to predict the presence of esophageal varices especially when they are large and risky.