North End fans will have fond recent memories of the Bees trip to Deepdale in February 2017, as their side came out on top in a six-goal thriller in PR1.
It was Aiden McGeady's double who helped the Lilywhites beat Brentford and secure their first win in five Championship matches.
Tom Field headed the Bees into an early lead, but McGeady levelled with a 20-yard strike, and Callum Robinson tapped in to put the Lilywhites ahead.
McGeady curled in a fine shot for his second before Daryl Horgan slotted in his first PNE goal.
Maxime Colin scored a late consolation for Brentford when his deflected late effort went in off the bar.
The victory ended a run of six successive defeats for Preston against the Bees and maintained their strong run of form at Deepdale, where they had lost just twice in the last 13 Championship matches.
In-form Lasse Vibe was denied a fourth league goal in five matches for the visitors when he hit the post after the break, but Brentford could not recover the deficit and slipped two places to 15th.
Simon Grayson's North End side remained 11th, but within touching distance of the Play-Off places, seven points behind sixth-placed Sheffield Wednesday.
After the game manager Simon Grayson said: "Sometimes it doesn't go your way and sometimes you get a day like today where everything you hit is a sweet connection and give the goalkeeper no chances.
"People talked leading up to the game about the record that we've got against Brentford, but records are there to be broken. I thought we knew what we had to do.
"We did things better off the ball, with the ball, and ultimately we're delighted to have won the game 4-2 but if you look at the chances, we could have had a few more."
Brentford boss Dean Smith added: "I feel it's one missed because I felt we were well on top for an hour of the game really until they scored the third goal.
"We knew this would be tough, but now we've got Reading away and then Sheffield Wednesday the following Tuesday so we'll be on the road a bit. We have to make sure that we're better defensively. I was disappointed with our defensive organisation after the third goal. That's what's disappointing and annoying."
PNE line-up: Maxwell, Browning, Clarke, Huntington, Cunningham, Horgan (Johnson, 82), Pearson, Browne, McGeady (May, 87), Robinson (Barkhuizen, 69), Hugill. Subs not used: Lindegaard, Makienok, Beckford, Boyle.
Brentford line-up: Bentley, Colin, Dean, Bjelland, Field, Yennaris (Kerschbaumer, 76), Woods, McEachran (Sawyers, 76), Jota, Vibe, Jozefzoon (Canos, 56). Subs not used: Egan, Bonham, Clarke, Barbet.
Referee: Tony Harrington