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Ryan Ledson scored the decisive penalty in the third round after Timothy Castagne missed his shot for Fulham by sending it over the bar.
Earlier in the shootout, misses by Fulham's Jorge Cuenca and Preston's Kaine Kesler-Hayden had been canceled out.
Preston's victory meant that the shootout surpassed the previous record set by Derby County and Carlisle in 2016, when Derby won 14-13 in a shootout.
'As the shootout went on, with the scores tied at eight-all and nine-all, it made me more determined to win it because of the effort and commitment put in to get to penalties,' said a player.
'We were the team, especially in injury time, trying to get the game to penalties.
It was a great atmosphere.
We'll look forward to the draw, but we have to park it and focus on other things now.
'Ledson put Preston ahead after 35 minutes with a first-time strike from the edge of the box that nestled into the bottom corner.
Kesler-Hayden had a low diving header brilliantly saved by the away goalkeeper Steven Benda as the home side impressed.
Tom Cairney played in Ryan Sessegnon, whose cross was swept home at the near post by Nelson on his first start for the club.
However, a Fulham side with all 11 players changed from the weekend draw with West Ham looked disjointed at times and missed several chances in normal time.
Castagne's whipped ball into the box was sent over the bar by Rodrigo Muniz, who put too much power on his effort, and Harrison Reed's fierce strike came off the crossbar, with Muniz unable to convert the rebound.
These misses ultimately proved costly as last season's semi-finalists exited the competition in the most dramatic of shootouts.
After the opportunity to rate players closed, the score displayed represented the average from all submissions by BBC Sport users.
The final score was Preston North End 1 (16), Fulham 1 (15).
Ryan Ledson (Preston North End) converted the winning penalty with a right-footed shot to the bottom left corner.