OBJECTIVE: Identify risk factors that could increase progression to severe disease and mortality in hospitalized SARS-CoV-2 patients in the Southeast US. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, retrospective cohort including 502 adults hospitalized with laboratory-confirmed COVID-19 between March 1, 2020 and May 8, 2020 within one of 15 participating hospitals in 5 health systems across 5 states in the Southeast US. METHODS: The study objectives were to identify risk factors that could increase progression to hospital mortality and severe disease (defined as a composite of intensive care unit admission or requirement of mechanical ventilation) in hospitalized SARS-CoV-2 patients in the Southeast US. RESULTS: A total of 502 patients were included, and the majority (476/502, 95%) had clinically evaluable outcomes. Hospital mortality was 16% (76/476), while 35% (177/502) required ICU admission, and 18% (91/502) required mechanical ventilation. By both univariate and adjusted multivariate analysis, hospital mortality was independently associated with age (adjusted odds ratio [aOR] 2.03 for each decade increase, 95% CI 1.56-2.69), male sex (aOR 2.44, 95% CI: 1.34-4.59), and cardiovascular disease (aOR 2.16, 95% CI: 1.15-4.09). As with mortality, risk of severe disease was independently associated with age (aOR 1.17 for each decade increase, 95% CI: 1.00-1.37), male sex (aOR 2.34, 95% CI 1.54-3.60), and cardiovascular disease (aOR 1.77, 95% CI 1.09-2.85). CONCLUSIONS: In an adjusted multivariate analysis, advanced age, male sex, and cardiovascular disease increased risk of severe disease and mortality in patients with COVID-19 in the Southeast US. In-hospital mortality risk doubled with each subsequent decade of life.