Background/aims Limited data exists on the outcomes of COVID-19 patients presenting with altered mental status (AMS). Hence, we studied the characteristics and outcomes of hospitalized COVID-19 patients who presented with AMS at our hospital in rural southwest Georgia. Methods Data from electronic medical records of all hospitalized COVID-19 patients from March 2, 2020, to June 17, 2020, were analyzed. Patients were divided in 2 groups, those presenting with and without AMS. Primary outcome of interest was in-hospital mortality. Secondary outcomes were needed for mechanical ventilation, need for intensive care unit (ICU) care, need for dialysis, and length of stay. All analyses were performed using SAS 9.4 and R 3.6.0. Results Out of 710 patients, 73 (10.3%) presented with AMS. Majority of the population was African American (83.4%). Patients with AMS were older and more likely to have hypertension, chronic kidney disease (CKD), cerebrovascular disease, and dementia. Patients with AMS were less likely to present with typical COVID-19 symptoms, including dyspnea, cough, fever, and gastrointestinal symptoms. Predictors of AMS included age ≥ 70 years, CKD, cerebrovascular disease, and dementia. After multivariable adjustment, patients with AMS had higher rates of in-hospital mortality (30.1% vs 14.8%, odds ratio (OR) 2.139, p = 0.019), ICU admission (43.8% vs 40.2%, OR 2.59, p < 0.001), and need for mechanical ventilation (27.4% vs 18.5%, OR 2.06, p = 0.023). Patients presenting with AMS had increased length of stay. Conclusions Patients with COVID-19 presenting with AMS are less likely to have typical COVID-19 symptoms, and AMS is an independent predictor of in-hospital mortality, need for ICU admission, and need for mechanical ventilation.