Aims The aim of this study was to test whether a newly designed polypharmacy‐based scale would perform better than Charlson's Comorbidity Index (CCI) to predict outcomes in chronic complex adult patients after a reference Emergency Department (ED) visit. Methods We built a polypharmacy‐based scale with prespecified drug families. The primary outcome was 6‐month mortality after the reference ED visit. Predefined secondary outcomes were need for hospital admission, 30‐day readmission, and 30‐day and 90‐day mortality. We evaluated the ability of the CCI and the polypharmacy‐based scale to independently predict 6‐month mortality using logistic regression, receiver operating characteristic (ROC) curves, and cumulative survival curves using Kaplan–Meier estimates and the log‐rank test for three‐category distributions of the polypharmacy‐based scale and the CCI. Finally, we sought to replicate our results in two different external validation cohorts. Results We included 201 patients (53.7% women, mean age = 81.4 years), 162 of whom were admitted to the hospital at the reference ED visit. In separate multivariable analyses accounting for gender, age and main diagnosis at discharge, both the polypharmacy‐based scale (P < .001) and the CCI (P = .005) independently predicted 6‐month mortality. The polypharmacy‐based scale performed better in the ROC analyses (area under the curve AUC = 0.838, 95% confidence interval CI = 0.780–0.896) than the CCI (AUC = 0.628, 95% CI = 0.548–0.707). In the 6‐month cumulative survival analysis, the polypharmacy‐based scale showed statistical significance (P < .001), whereas the CCI did not (P = .484). We replicated our results in the validation cohorts. Conclusions Our polypharmacy‐based scale performed significantly better than the CCI to predict 6‐month mortality in chronic complex patients after a reference ED visit.