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There is limited information on predicting incident cardiovascular outcomes among high- to very high-risk populations such as the elderly (≥ 65 years) in the absence of prior cardiovascular disease and the presence of non-cardiovascular multi-morbidity. We hypothesized that statistical/machine learning modeling can improve risk prediction, thus helping inform care management strategies. We defined a population from the Medicare health plan, a US government-funded program mostly for the elderly and varied levels of non-cardiovascular multi-morbidity. Participants were screened for cardiovascular disease (CVD), coronary or peripheral artery disease (CAD or PAD), heart failure (HF), atrial fibrillation (AF), ischemic stroke (IS), transient ischemic attack (TIA), and myocardial infarction (MI) for a 3-yr period in the comorbid history. They were followed up for up to 45.2 months. Analyses included descriptive approaches in terms of incidence rates and density ratios, and inferential in terms of main effect statistical/complex machine learning modeling. The contemporary risk factors of interest spanned across the domains of comorbidity, lifestyle, and healthcare utilization history. The cohort consisted of 154,551 individuals (mean age 68.8 years; 62.2% female). The overall crude incidence rate of CVD events was 9.9 new cases per 100 person-years. The highest rates among its component outcomes were obtained for CAD or PAD (3.6 for each), followed by HF (2.2) and AF (1.8), then IS (1.3), and finally TIA (1.0) and MI (0.9).Model performance was modest in terms of discriminatory power (C index: 0.67, 95%CI 0.667-0.674 for training; and 0.668, 95%CI 0.663-0.673 for validation data), equal agreement between predicted and observed events for calibration purposes, and good clinical utility in terms of a net benefit of 15 true positives per 100 patients relative to the All-patient treatment strategy. Complex models based on machine learning algorithms yielded incrementally better discriminatory power and much improved goodness-of-fitness tests from those based on main effect statistical modeling. This Medicare population represents a highly vulnerable group for incident CVD events. This population would benefit from an integrated approach to their care and management, including attention to their comorbidities and lifestyle factors, as well as medication adherence., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)