Abstract Background The PROFUND index (PI) is a prognostic scale for polypathological patients at 12 months. The objective of the study was to validate the PI as a predictor of 1-year mortality in a current cohort of polypathological patients and analyse its prognostic usefulness in the short-term (1 month and 3 months) after discharge from Internal Medicine. Design We conducted a prospective observational study and all polypathological patients discharged from an Internal Medicine Department between 01 March 2016 and 28 February 2017 were enrolled. Methods The variables recorded for each patient were age, sex, diseases and diagnostic categories defining patients as polypathological patients, PI at discharge, number of hospital admissions, length of stay, vital status at 1 year, and date and place of death if applicable. Follow-up lasted 1 year from the time of enrolment. Results Six hundred and ten polypathological patients were enrolled. Mortality was 41% and the patients who died were older, their length of stay was longer and their PI was higher compared with those who survived. The discrimination of the PI for predicting mortality was good, with a C-statistic of 0.718 [95% confidence interval (CI) 0.67–0.76]. In addition, a subgroup of patients with early mortality after discharge was identified, with a C-statistic of 0.74 (95% CI 0.67–0.80) at 30 days and 0.73 (95% CI 0.68–0.78) at 90 days. Conclusions The PI is a valid tool for predicting early and 1-year mortality in polypathological patients after discharge from Internal Medicine.