To prevent wound dehydration and bacterial penetration, a wound dressing should be occlusive, but on the other hand it should also be permeable for wound exudate to prevent bullae formation. To meet these requirements a new type of polyurethane wound dressing which consists of a microporous top layer (pore size < 0.7 m) supported by a sublayer with a highly porous sponge-like structure containing micropores (pore size <10 m) as well as macropores (pore size: 50-100 m) was designed. The pores of both layers are interconnected and form a continuous structure in the membrane. Membranes according to this design were prepared either by means of a two-step or by means of a one-step casting process. Both fabrication methods are based on phase inversion techniques. Asymmetric polyurethane Biomer® membranes prepared by the two-step casting process were tested in vivo as full thickness skin substitutes using guinea pigs. Neither wound dehydration nor infections were observed while the drainage capacity of the wound dressing was effective in preventing bullae formation. Furthermore the wound dressing remained firmly adhered to the wound surface during the whole process of wound healing. In contrast to all other commercial wound dressings currently available the polyurethane wound dressing applied on excised clean wounds did not need to be replaced during healing but could be left on the wound until full regeneration of the skin had taken place after which it was spontaneously repelled.