The 1,000-bed hospital ship pushed off from Pier 90 on the West Side on Thursday afternoon as first responders cheered and saluted.
The Naval hospital ship first arrived on March 30.
It was originally sent to care for patients without COVID-19, but it started accepting coronavirus patients a week later.
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It treated a total of 182 people.
All of the patients have now been discharged or transferred.
The Comfort is scheduled to return to Norfolk, Virginia. It will be disinfected and restocked for its next mission.