The Slovakian, ranked 111th in the world, recovered from losing the first set to claim a 2-6, 6-1, 6-2 win which denied Fognini, ranked 13th in the world, his third straight title in Germany having won last season's Hamburg and Stuttgart tournaments.
The 24-year-old Klizan, whose only previous ATP tournament win was in St Petersburg in 2012, deserved his clay-court title having beaten Russian third-seed Mikhail Youzhny in the second round, then defending champion and second-seed Tommy Haas in Saturday's semi-final.
"I felt very bad and took two tablets because of stomach cramps after the first set," revealed Klizan.
"That was a crazy game from both of us."
After losing the first set, Klizan regained his composure to race into a 4-1 lead in the second, then dominated the third to go 3-0 up before Fognini pulled two games back, but the Slovakian held his service to take the title.
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