Whenever the party tries to sleep in an inn, throw loud raucous parties that keep them up all night.
Whenever the party tries to buy a magic item, kill the person who's supposed to sell it to them so the party never gets new items. Or kill the person who did sell the item and make sure word gets around, so no one will sell to the party.
Hire the town drunk to put "the moves" on someone in the party.
Frame the party.
Start nasty rumors about the party.
Use "Bestow Curse" on waiters so the waiters don't notice the party.
Raise the dead on any big bad the party just killed.
Take the credit for any big bad the party just killed.
Slip drugs into the party's food/drink.