Background: Patients suffering from coronavirus disease-19 (COVID-19)-related interstitial pneumonia have variable outcomes, and the risk factors for a more severe course have yet to be comprehensively identified. Cohort studies have suggested that coronary artery calcium (CAC), as estimated at chest computed tomography (CT) scan, correlated with patient outcomes. However, given that the prevalence of CAC is gender- and age-dependent, the influence of baseline confounders cannot be completely excluded. Methods: We designed a retrospective, multicenter case-control study including patients with COVID-19, with severe course cases selected based on death within 30 days or requiring invasive ventilation, whereas controls were age- and sex-matched patients surviving up to 30 days without invasive ventilation. The primary outcome was the analysis of moderate-to-severe CAC prevalence between cases and controls. Results: A total of 65 cases and 130 controls were included in the study. Cases had a significantly higher median pulmonary severity score at chest CT scan compared to controls (10 vs. 8, respectively; p = 0.0001), as well as a higher CAC score (5 vs. 2; p = 0.009). The prevalence of moderate-to-severe CAC in cases was significantly greater (41.5% vs. 23.8%; p = 0.013), a difference mainly driven by a higher prevalence in those who died within 30 days (p = 0.000), rather than those requiring invasive ventilation (p = 0.847). White blood cell count, moderate-to-severe CAC, the need for antibiotic therapy, and severe pneumonia at CT scan were independent primary endpoint predictors. Conclusions: This case-control study demonstrated that the CAC burden was higher in COVID-19 patients who did not survive 30 days or who required mechanical ventilation, and CAC played an independent prognostic role.