Disclosed herein is a biological surgical patch having minimal immunerejection with goodbiocompatibility, along with safe/reliable application thereof, and a methodof preparation thereof.The biological surgical patch comprises a substrate prepared from a naturalanimal tissue; the patchis made by a method that includes the steps of crosslinking and fixing thesubstrate, minimizingantigens from the substrate, tanning the substrate, and incorporating anactive layer in the substrate.Cross-linking and fixing may be accomplished by using an epoxy compound thathas a hydrocarbonbackbone, that is water-soluble, and which does not contain an ether or esterlinkage in its backbone.Reagents are used to block specific active groups in protein molecules of thesubstrate, in order tominimize the antigens therein. Tanning is achieved preferably by graftingpolymers onto collagenmolecules of the substrate. The active layer preferably comprises apolypeptide orglycosaminoglycan.