Police assume the theft took place between Saturday night and Sunday morning.
A cloth with a drop of Pope John Paul II's blood was stolen from Cologne Cathedral in western Germany at the weekend, police said.
"Its material value is small but the spiritual loss is much greater," the cathedral's provost, Gerd Bachner, was quoted in the police statement from Sunday as saying.
Bachner urged the thieves to "come to their senses" and return the relic.
A visitor to cathedral noticed early Sunday that the cloth was missing from its glass case, which was built to recall a visit by the pontiff to Cologne in November 1980.
Police released a picture of the glass with a hole smashed by the thieves.
Police assume the theft took place between Saturday night and Sunday morning. Pope John Paul II led the Catholic church from 1978 until his death in 2005.