The invention relates to a methods and compositions for treating a surface, suspension or solution contaminated with a PrPSc prion protein or a surrogate thereof. The methods and compositions employ a combination of one or more enzymes effective to cleave a prion protein to fragments having a non-infective molecular weight, and one or more agents selected to favor conformational unfolding of the PrPSc prion protein while not denaturing the one or more enzymes.
