PURPOSE Early identification of patients who may be at high risk of significant weight loss (SWL) is important for timely clinical intervention in lung cancer radiotherapy (RT). A clinical decision support system (CDSS) for SWL prediction was implemented within the routine clinical workflow and assessed on a prospective cohort of patients. MATERIALS AND METHODS CDSS incorporated a machine learning prediction model on the basis of radiomics and dosiomics image features and was connected to a web-based dashboard for streamlined patient enrollment, feature extraction, SWL prediction, and physicians' evaluation processes. Patients with lung cancer (N = 37) treated with definitive RT without prior RT were prospectively enrolled in the study. Radiomics and dosiomics features were extracted from CT and 3D dose volume, and SWL probability (≥ 0.5 considered as SWL) was predicted. Two physicians predicted whether the patient would have SWL before and after reviewing the CDSS prediction. The physician's prediction performance without and with CDSS and prediction changes before and after using CDSS were compared. RESULTS CDSS showed significantly better prediction accuracy than physicians (0.73 v 0.54) with higher specificity (0.81 v 0.50) but with lower sensitivity (0.55 v 0.64). Physicians changed their original prediction after reviewing CDSS prediction for four cases (three correctly and one incorrectly), for all of which CDSS prediction was correct. Physicians' prediction was improved with CDSS in accuracy (0.54-0.59), sensitivity (0.64-0.73), specificity (0.50-0.54), positive predictive value (0.35-0.40), and negative predictive value (0.76-0.82). CONCLUSION Machine learning–based CDSS showed the potential to improve SWL prediction in lung cancer RT. More investigation on a larger patient cohort is needed to properly interpret CDSS prediction performance and its benefit in clinical decision making.