Background: The Hospital-University Institute (IHU) Méditerranée Infection features a 27,000 square meter building hosting 700 employees and 75 hospitalized patients in the center of Marseille, France. Method: Previous preparedness in contagious disease management allowed the IHU to manage the COVID-19 outbreak by continuing adaptation for optimal diagnosis, care and outcome. We report here the output of this management. Results: From 5 March 2020, and 26 April 2021, 608,313 PCR tests were provided for 424,919 patients and 44,089 returned positive. A total of 23,390 patients with COVID-19 were followed at IHU with an overall case fatality ratio of 1.7%. Of them 20,270 were followed as outpatients with an overall CFR of 0.17%. We performed 24,807 EKG, 5759 low dose CT Scanner, and 18,344 serology. Of the 7643 nasopharyngeal samples inoculated in cell cultures 3317 (43.3%) yielded SARS-Cov-2 isolates. Finally, 7370 SARS-Cov-2 genomes were analyzed, allowing description of the first genetic variants and their implication in the epidemiologic curves. Continuous clinical care quality evaluation provided the opportunity for 155 publications allowing a better understanding of the disease and improvement of care and 132 videos posted on the IHU Facebook network, totaling 60 million views and 390,000 followers, and dealing with COVID-19, outbreaks, epistemology, and ethics in medicine. Conclusions: During this epidemic, IHU Méditerranée Infection played the role for which it has been created; useful clinical research to guarantee a high-quality diagnostic and care for patient and a recognized expertise.