Introduction: The comorbidity-polypharmacy score (CPS) is a simple sum of pre-admission medications and comorbid conditions. Previous studies show that CPS correlates with morbidity, mortality, readmissions, adverse events, and acuity level determinations in various patient populations. The aim of this study is to determine the behavior of CPS across a large sample of medicalsurgical patients, inclusive of all age ranges. We hypothesized that CPS will be associated with readmissions, mortality, and hospital length of stay. Methods: We performed an IRB-exempt study of patients admitted to a sixhospital network between Jul 2014-Dec 2014. Variables analyzed included demographics (age, gender); polypharmacy data (number of pre-admission medications); comorbid conditions (all “pre-existing” conditions on admission); hospital length of stay (HLOS); need for ICU; discharge to home versus nursing facility; and mortality. Descriptive and univariate analyses were performed using 3-point CPS increments, with mortality, readmissions, and HLOS as primary end-points. Subsequent multivariate analyses were performed for variables reaching significance level of p<0.10 in univariate analyses. SPSS 18 Statistics (IBM, Armonk, NY) was used, with statistical significance set at α < 0.01 due to multiple comparisons. Results: A total of 20,644 medical-surgical patients were studied. In univariate analyses, CPS was significantly associated with patient age, gender, length of stay, readmission, discharge destination, ICU requirement, and mortality (all, p<0.001). On multivariate analyses, factors independently associated with mortality included age (OR 1.03 per year); CPS (OR 1.05 per unit); and need for ICU (OR 21.9). Factors independently associated with readmission included age (OR 1.01 per year) and CPS (OR 1.04 per unit). ICU stay was not a predictor of readmission after correcting for index admission mortality. Conclusions: We found that CPS is independently associated with readmissions and mortality across all age groups. Further research in this area is warranted, with focus on CPS as a potential frailty indicator, as well as contributions of specific comorbidities and/or medication classes to the overall risk of mortality or readmission. CPS appears to provide a reasonable platform for patient risk stratification based on easily obtainable clinical data inputs.