Spain's Feliciano Lopez sent the Australian ninth seed spinning out of the Madrid Masters on a night of surprises.
The win put 21-year-old Fish, a childhood friend of Andy Roddick, into the top 20 of the ATP's entry rankings system.
American Mardy Fish's hopes of putting aside his troublesome heart condition to compete in his first grand slam tournament in 12 months ended on Wednesday after the former top-ten player was forced to pull out of next week's U.S. Open.