The audio recording reportedly featuring IS spokesman Abu Mohamed al-Adnani was posted online yesterday after much fanfare by IS supporters on Twitter.
"Will we be defeated if we lose Mosul, or Sirte, or Raqa, or all the cities, and go back to how we were before?" Adnani said.
The three cities are IS's strongholds in Iraq, Libya, and Syria respectively.
"No. Defeat is only losing the desire and the will to fight," Adnani continued, in his first voiced speech since October.
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He said even "20,000 air strikes" by the coalition had not destroyed IS.
Adnani also called for attacks on the US and Europe during the holy month of Ramadan, which starts in early June this year, an appeal he made at the same time last year when urging supporters to seek "martyrdom".
On Friday, flyers apparently dropped by the coalition on Raqa city in northern Syria urged residents to leave the city, perhaps ahead of an offensive by anti-IS forces to recapture it.
IS has seized swathes of territory in Syria and Iraq to create a self-styled "caliphate." Its leader, Abu Bakr al-Baghdadi, has received pledges of alliance from jihadist groups around the world.