Objectives: Develop and evaluate a pre-deployment sequestration (PDS) protocol to prevent SARS-CoV-2 cases on board the USS RONALD REAGAN (CVN-76). Methods: The USS RONALD REAGAN includes a crew of approximately 3,000 Sailors and an embarked Air Wing of 2,000 personnel. The PDS was conducted in three waves of 14-day strict quarantines during the months of April and May 2020. Sailors were cleared to board the ship with two negative rtPCR tests at days 14 and 16. The ship was sanitized prior to Wave 1 boarding. Results: From March 1, 2020 through May 31, 2020, a total of 51 SARS-CoV-2 positive cases were detected. During the three waves of PDS, 28 Sailors were found to be positive on exit testing (14, 11, and 3, respectively); no cases were found among the Air Wing. During the first 90 days at sea, no SARS-CoV-2 cases were detected among any of the embarked personnel. Conclusions: Although resource-intensive, the PDS protocol implemented for USS RONALD REAGAN resulted in a COVID-free ship during a global pandemic with unprecedented scope. Elements of this pandemic PDS protocol may be useful in other highly risk-averse environments with no tolerance for COVID-19 infections.