We aimed to examine the performance of the distress thermometer (DT) and identify the prevalence and risk factors associated with psychological distress (PD) in heterogeneous cancer patients. This cross-sectional study enrolled 1496 heterogeneous cancer patients from the inpatient and outpatient departments. Receiver operating characteristic analysis (ROC) of DT was evaluated against the Hospital Anxiety and Depression Scale-Total (HADS-T ≥15). An area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and clinical utility index were calculated. Multiple binary logistic regression was used to identify the factors associated with PD. Referring to ROC analysis, DT showed good discriminating accuracy (AUC = 0.88). A cutoff score of 4 was established, and it yielded sensitivity (0.81), specificity (0.88), PPV (0.87), NPV (0.82), and clinical utility indexes (screening utility = 0.71 and case-finding utility = 0.73). 46.5% of our participants was distressed. Lower education levels (odd ratio (OR) = 1.39), advanced stage (OR = 1.85), active disease status (OR = 1.82), lack of exercise (OR = 3.03), diagnosis known (OR = 0.64), emotional problems (OR = 3.54), and physical problems (OR = 8.62) were the predictive factors for PD. DT with a cutoff score (≥4) is a comprehensive, appropriate, and practical initial screener for PD in cancer patients. Predicting factors should be considered together for effective management of PD in such population. Copyright © 2020 Sudip Thapa et al.