Background: Originating in Wuhan, China, SARS-Cov 2 (COVID-19) has since spread across the globe. Numerous patient characteristics and co-morbidities have been associated with COVID-19 severity and mortality, though most studies have occurred outside the United States and many have utilized relatively small sample sizes. The present study investigated factors related to mortality using a large and diverse sample of COVID-19 patients hospitalized in Massachusetts.Methods: Multi-site retrospective cohort study of 4,227 patients with laboratory-confirmed COVID-19 who were admitted to a hospital and either discharged or died by July 17, 2020. Hospitalization occurred within Mass General Brigham, a healthcare system which includes two academic medical centers, community and specialty hospitals, a large physician network, and other health care entities across the Commonwealth of Massachusetts. Demographic, clinical, and pharmacological data were extracted from electronic health records. Multivariable logistic regression analyses were utilized to investigate factors associated with COVID-19 mortality.Findings: 17,971 patients had tested positive for COVID-19 within the Mass General Brigham system. Of those, 4,227 (23·5%) patients had been admitted to hospital and either expired or discharged. Of the patients hospitalized, there were 3,674 (86%) who discharged and 553 (14%) who died. The mean age was 60·6 (SD = 19·1) and 53·1% were male. Of 2669 (63·1%) cases having at least one co-morbidity, 439 (16·5%) of those cases resulted in death. In multivariate logistic regression analysis, factors associated with mortality were age 75 years or older (odds ratio [OR] = 6·98, 95% CI: 4·13, 11·79), age 65-74 years old (OR = 3·22, 95% CI: 1·90, 5·45), male sex (OR = 1·58, 95% CI: 1·25, 2·00), blood cancer (OR = 2·00, 95% CI: 1·10, 3·63), chronic kidney disease (OR = 1·38, 95% CI: 1·05, 1·81), history of stroke (OR = 1·51, 95% CI: 1·09, 2·10), congestive heart failure (OR = 1·70, 95% CI: 1·26, 2·29), SSRI use (OR = 1·86, 95% CI: 1·15, 2·98), and BMI of 40+ (OR = 1·91, 95% CI: 1·19, 3·06). Subgroup analyses revealed COPD (OR = 1·62, 95% CI: 1·02, 2·57) as a unique risk factor for males and cardiovascular disease (OR = 2·57, 95% CI: 1·42, 4·63) and history of deep vein thrombosis or pulmonary embolism (OR = 2·83, 95% CI: 1·26, 6·36) for those under 65 years of age.Interpretation: Age and sex were the strongest demographic predictors of mortality. Many of the factors associated with mortality in the present study are also related to inflammation and hypercoagulability. The presence of these comorbidities and characteristics likely contribute to mortality risk, given that COVID-19 has been independently found to affect the hematologic system. It would be prudent to give special consideration to COVID-19 patients who have these characteristics or pre-existing conditions, when making decisions regarding treatment and level of care.Funding: None applicable.Declaration of Interests: None declared by all authors.Ethics Approval Statement: As the analyses were conducted for quality improvement and the report involves routinely collected and de-identified data, no ethical approval was required.