ABSTRACT: The optimal methodology for assessing comorbidity to predict various surgical outcomes such as mortality, readmissions, complications, and failure to rescue (FTR) using claims data has not been established.Compare diagnosis-based and prescription-based comorbidity scores for predicting surgical outcomes.We used 100% Texas Medicare data (2006-2011) and included patients undergoing coronary artery bypass grafting, pulmonary lobectomy, endovascular repair of abdominal aortic aneurysm, open repair of abdominal aortic aneurysm, colectomy, and hip replacement (N=39,616). The ability of diagnosis-based [Charlson comorbidity score, Elixhauser comorbidity score, Combined Comorbidity Score, Centers for Medicare and Medicaid Services-Hierarchical Condition Categories (CMS-HCC)] versus prescription-based Chronic disease score in predicting 30-day mortality, 1-year mortality, 30-day readmission, complications, and FTR were compared using c-statistics (c) and integrated discrimination improvement (IDI).The overall 30-day mortality was 5.8%, 1-year mortality was 17.7%, 30-day readmission was 14.1%, complication rate was 39.7%, and FTR was 14.5%. CMS-HCC performed the best in predicting surgical outcomes (30-d mortality, c=0.797, IDI=4.59%; 1-y mortality, c=0.798, IDI=9.60%; 30-d readmission, c=0.630, IDI=1.27%; complications, c=0.766, IDI=9.37%; FTR, c=0.811, IDI=5.24%) followed by Elixhauser comorbidity index/disease categories (30-d mortality, c=0.750, IDI=2.37%; 1-y mortality, c=0.755, IDI=5.82%; 30-d readmission, c=0.629, IDI=1.43%; complications, c=0.730, IDI=3.99%; FTR, c=0.749, IDI=2.17%). Addition of prescription-based scores to diagnosis-based scores did not improve performance.The CMS-HCC had superior performance in predicting surgical outcomes. Prescription-based scores, alone or in addition to diagnosis-based scores, were not better than any diagnosis-based scoring system.