The agency won the SAB Miller account for Miller Lite just over a year ago.
It follows a shake-up of the roster last year i n which Wieden & Kennedy was dropped from the Miller roster after 10 years. That split followed another with roster agency The Martin Agency.
The Miami-based Crispin Porter, which is part of MDC Partners, has created work for Miller Lite as well as the Miller High Life brands. Most recently, it created "man laws", a spot starring Burt Reynolds for Miller Lite. However, this failed to lift sales of the beer and the last ads Miller aired for its Lite beer brand were created internally.
Last year, Miller spent around $148m on Miller Lite and less than $10m on Miller High Life work, according to TNS Media Intelligence.
Alex Bogusky, chief creative officer of Crispin Porter, said: "We just have fundamental differences over creative and strategy. And although we made every attempt to find common ground, the process of multi-layered approvals of creative and strategy has made doing work we can be proud of increasingly difficult. So it seems to be in the best interest of both parties to part ways."
A spokesman for Miller said: "We appreciate the work Crispin has done for Miller and we wish them all the best."
Two weeks ago, Cripsin Porter emerged as the frontrunner to pick up several key Nike accounts after Wieden & Kennedy lost several pieces of business.