Background: large studies on the predictive role of chronic conditions on mortality from COVID‑19 are scarce. We developed a predictive model of death from COVID‑19 in an Italian cohort aged 40 years or older.Methods: we conducted a cohort study on prospectively collected data. The cohort included all (n=18,286) swab positive cases ≥40 year-old in patients registered with the Agency for Health Protection (AHP) of Milan up to 27/04/2020. Data on comorbidities were obtained from the chronic condition administrative database of the AHP. A multivariable logistic regression model, including age and gender and the selected conditions, was fitted to predict 30-day mortality risk and internally validated. External validation and recalibration were performed in a cohort of untested subjects with COVID-19 like symptoms. R software was used for the analysis.Results: chronic conditions having the largest model-adjusted odds ratio (OR) of dying within 30 days from COVID-19 infection were chronic heart failure (OR=1.9, 95%CI 1.5-2.5), tumors (OR=1.8, 95%CI 1.4-2.3), complicated diabetes (OR=1.6, 95%CI 1.1-2.2) and dialysis-dependent chronic kidney disease (OR=1.5, 95%CI 1.0-2.2). Bootstrap-validated c-index was 0.78. The model fitted on the validation cohort had a c-index of 0.93, but required recalibration. With this latter model, at a 10% risk of death threshold, 11% of the AHP population aged 40 years or older is considered at high risk.Conclusion: we identified a selected number of comorbidities predicting early risk of death in a large COVID-19 cohort aged 40 years or older. In a new epidemic wave, our results will help physicians and health systems to identify high-risk subject to target for prevention and therapy in this specific age group.