Izzie made her final appearance in the sixth season, leaving Seattle after Alex refused to resume their marriage. Heigl requested to be released from her contract 18 months early, in order to spend more time with her family. 10 years after her final appearance, the character's fate was revealed in a season 16 episode.

How did Izzie leave GREY's anatomy?

Soon after she returned to work, she made an unforgivable mistake, accidentally administering the incorrect dosage of medicine to one of her patients. The debacle got her fired from the job. She blamed her husband, Alex, for snitching on her. They broke up.

Why did Izzie leave in Season 5?

After beating cancer but being fired by Webber, Izzie left but then came back for a final scan to make sure she was totally cancer-free. She was clearly interested in reconciling with Alex, and met him to show off the results of her scan.