The historic moment, which happened at 23:00 GMT, was marked by both celebrations and anti-Brexit protests.
In a message released on social media an hour before the UK's departure, the prime minister said: "For many people this is an astonishing moment of hope, a moment they thought would never come.
"And there are many of course who feel a sense of anxiety and loss."
He said some had worried the political "wrangle" would not end but it was his job to take the country forward.
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