Background: National data from diverse institutions across the United States are critical for guiding policymakers as well as clinical and public health leaders. This study characterized a large national cohort of patients diagnosed with COVID-19 in the U.S., compared to patients diagnosed with viral pneumonia MESHD pneumonia HP and influenza. Methods and Findings: We captured cross-sectional information from 36 large healthcare systems in 29 U.S. states, participating in PCORnet, the National Patient-Centered Clinical Research Network. Patients included were those diagnosed with COVID-19, viral pneumonia MESHD pneumonia HP and influenza in any care setting, starting from January 1, 2020. Using distributed queries executed at each participating institution, we acquired information for patients on care setting (any, ambulatory, inpatient or emergency MESHD department, mechanical ventilator), age TRANS, sex, race, state, comorbidities (assessed with diagnostic codes), and medications used for treatment of COVID-19 (hydroxychloroquine with or without azithromycin; corticosteroids, anti-interleukin-6 agents). During this time period, 24,516 patients were diagnosed with COVID-19, with 42% in an emergency MESHD department or inpatient hospital setting; 79,639 were diagnosed with viral pneumonia MESHD pneumonia HP (53% inpatient/ED) and 163,984 with influenza (41% inpatient/ED). Among COVID-19 patients, 68% were 20 to <65 years of age TRANS, with more of the hospitalized/ED patients in older age TRANS ranges (23% 65+ years vs. 12% for COVID-19 patients in the ambulatory setting). Patients with viral pneumonia MESHD pneumonia HP were of a similar age TRANS, and patients with influenza were much younger. Comorbidities were common, especially for patients with COVID-19 and viral pneumonia MESHD pneumonia HP, with hypertension MESHD hypertension HP (32% for COVID-19 and 46% for viral pneumonia MESHD pneumonia HP), arrhythmias HP (20% and 35%), and pulmonary disease MESHD (19% and 40%) the most common. Hydroxychloroquine was used in treatment for 33% and tocilizumab for 11% of COVID-19 patients on mechanical ventilators (25% received azithromycin as well). Conclusion and Relevance: PCORnet leverages existing data to capture information on one of the largest U.S. cohorts to date of patients diagnosed with COVID-19 compared to patients diagnosed with viral pneumonia MESHD pneumonia HP and influenza.