PSV Eindhoven's Eredivisie title bid suffered a huge setback as second-half goals from Sander Duits and Mitchell Schet gave RKC Waalwijk a shock win at Mandemakers Stadium.
Jan Vennegoor of Hesselink grabbed a late consolation for the visitors, but it was not enough to prevent Phillip Cocu's men finishing the evening seven points adrift of leaders Ajax following the champions' 5-0 win at Heerenveen.
The result was equally crucial for the hosts, who boosted their chances of reaching the play-off places for a slot in next season's Europa League by moving level on points with eighth-placed NEC Nijmegen.
The visitors had a number of counter-attacking chances early on but never looked sharp against a well-organised and tight Waalwijk side, whose goalkeeper Jeroen Zoet was rarely tested.
Duits made space in the box to fire the opener past Przemyslaw Tyton in the 55th minute and just two minutes later Schet's deflected shot into the box deceived PSV's Polish keeper.
Jeremain Lens had little luck up front for PSV but Vennegoor of Hesselink gave his side hope when he struck home four minutes from time, sparking a late but fruitless quest for an equaliser.
PSV suffered another blow with the enforced substitutions of both Kevin Strootman and Erik Pieters due to injuries, with doubts now over whether they will be fit to face AZ Alkmaar at home on Saturday.