Columbia's Greipel managed his first success of the three-week race in the 18th stage after prevailing in a bunched finish through the tight streets of the northern Italian city of Brescia.
Greipel had been hoping for several stage wins this year but bad weather hit most of the other sprint sections, where he was squeezed out anyway, and a raft of mountain stages also offered little hope for the specialists.
He completed the 156-km downhill route from Levico in three hours 14 minutes 59 seconds ahead of New Zealand's Julian Dean and Italian Tiziano Dall'Antonia.
Spain's Caisse d'Epargne rider Arroyo, who has never threatened overall victory in a Grand Tour, was only just behind in the main pack to keep his two minute and 27 seconds advantage over second-placed Ivan Basso.
Basso, the 2006 winner, has been so pleased with his Giro that Liquigas announced on Thursday he would be staying with the team for another two years.
Two mountain stages follow on Friday and Saturday with the race finishing with a time trial in Verona on Sunday.
Friday's 195-km ride to Aprica goes via the Mortirolo peak and Saturday's 178-km stage from Bormio to Ponte di Legno-Tonale takes the riders up the Gavia mountain, where organizers hope lingering snow will not disrupt the route.
Arroyo, 30, is favorite for a surprise triumph although Astana leader Alexander Vinokourov, who lost bags of time after missing a breakaway in the second week, believes there could still be some twists in the tale.
"Mortirolo and Gavia will change the standings, you can attack at any moment. I've got the legs, you will see me ahead," the Kazakh, over five minutes off the pace, told reporters.
