It appears to have been taken during the burglary of a small chapel that was a place of special significance to Pope John Paul II.
The church of San Pietro della Ienca lies in an isolated spot in the mountains of central Abruzzo region.
Over the weekend, thieves broke some protective iron bars and forced their way in through a window.
They left the collection box, but took a crucifix and the priceless relic, which contains a piece of gauze once soaked in the blood of the late Pope – one of only three such relics in the world.
Members of the local cultural association supporting the chapel are distraught.
Pope John Paul II used to escape the pressures of life in the Vatican by coming to the mountains.
Dozens of police officers are now searching the area with sniffer dogs.
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