Non-invasive tools are needed to rule out the presence of esophageal varices (EV) in patients with chronic liver disease. The aim of this study was to evaluate diagnostic accuracy of Liver stiffness-spleen size-to-platelet ratio (LSPS) for EV detection and identification of high risk EV in patients with CLD. A total of 70 patients with CLD irrespective of the etiology attending at OPD and admitted in Department of Gastrointestinal, Hepatobiliary and Pancreatic Disorders (GHPD) of BIRDEM General Hospital, Dhaka, Bangladesh from January 2016 to October 2017 were enrolled in this observational cross-sectional study. All patients underwent routine laboratory tests, liver function tests, ultrasonography, liver stiffness (LS) measurement and esophagogastroduodenoscopy. Clinical value of LSPS was compared with platelet count, spleen size and LS for detection of esophageal varices. Diagnostic accuracy was assessed by the Area under the receiver operating characteristic (AUROC) curve. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated using ROC curve. LSPS has better diagnostic accuracy for detection of EV in terms of AUROC, showing superiority over each factor alone. LSPS also detect high risk EV but accuracy was lower than detection of EV. The optimal cutoff values of LSPS for EV and high risk EV were 0.879 and 4.132 respectively, at which AUROC, negative predictive value, and accuracy were 0.910 [95% confidence interval (CI) 0.832-0.988], 90.9% and 90.0% and 0.695 (95% CI 0.520-0.870), 62.5% and 69.4% respectively. LSPS represents a useful, noninvasive method to detect EV and a high risk EV in patients with CLD. Clinicians should recommend those patients with CLD who show higher values of LSPS to undergo further endoscopic examination.