Novel coronavirus disease 2019 (COVID-19) was commonly compared with influenza. The Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) conducted the study on the etiology and characteristics of U.S. hospitalized adults with influenza. It started enrollment of patients with COVID-19 hospitalizations in March 2020. Patients with influenza were compared with those with COVID-19 in the first months of the U.S. epidemic. Adults aged older than or equal to 18 years were admitted to hospitals in 4 sites with acute respiratory illness and analyzed by real-time reverse transcription-polymerase chain reaction for influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing COVID-19. Demographic and illness attributes were collected for influenza illnesses during 3 seasons, 2016–2019. Similar data were collected on COVID-19 cases admitted before June 19, 2020. Age groups hospitalized with COVID-19 (n=914) came out to be similar to those admitted with influenza (n=1937); studies showed 80% of patients with influenza, and 75% of patients with COVID-19 were aged older than or equal to 50 years. Deaths from COVID-19 that occurred in younger patients were less often associated with underlying conditions. White non-Hispanic persons were overrepresented in influenza (64%) compared with COVID-19 hospitalizations (37%). More severity and complications occurred with COVID-19 including more ICU admissions (AOR = 15.3 [95% CI: 11.6, 20.3]), ventilator use (AOR=15.6 [95% CI: 10.7, 22.8]), 7 additional days of hospital stayed in those discharged alive, and death during hospitalization (AOR=19.8 [95% CI: 12.0, 32.7]). While COVID-19 was seen to cause respiratory illness like influenza, it was found to be associated with significantly greater severity of illness, longer hospital stays, and higher in-hospital deaths.