Louisiana experienced high morbidity and mortality from COVID-19. To assess possible explanatory factors, we conducted a cohort study of patients hospitalized with COVID-19 in New Orleans during August 2020–September 2021. Following enrollment, we reviewed medical charts, and performed SARS-CoV-2 RT-PCR testing on nasal and saliva specimens. We used multivariable logistic regression to assess associations between patient characteristics and severe illness, defined as high-flow oxygen or intubation. Among 456 patients, median age was 56 years, 277 (60.5%) were Black non-Hispanic, 436 (95.2%) had underlying health conditions, and 358 were unvaccinated (92.0% of 389 verified). Overall, 187 patients (40.1%) had severe illness; 60 (13.1%) died during admission. In multivariable models, severe illness was associated with age ≥ 65 years (OR 2.08, 95% CI 1.22–3.56), hospitalization > 5 days after illness onset (OR 1.49, 95% CI 1.01–2.21), and SARS CoV-2 cycle threshold (Ct) result of < 32 in saliva (OR 4.79, 95% CI 1.22–18.77). Among patients who were predominantly Black non-Hispanic, unvaccinated and with underlying health conditions, approximately 1 in 3 patients required high-flow oxygen. Older age and delayed time to admission might have contributed to the high case-severity. An association between case-severity and low Ct value in saliva warrants further investigation.