We tested different biodegradable matrix materials as dermal substitutes in a porcine wound model. Matrixes were covered with a split-skin mesh graft and protected with a microporous, semipermeable membrane, which prevents blister formation, wound infection and provides ultimate healing conditions. Evaluation parameters were as follows: epithelization, dermal reconstitution, wound contraction, and cosmetic and functional aspect. A microfibrillar matrix of nondenatured collagen gave the best result, with immediate fibroblast ingrowth and epidermal outgrowth. Slight inflammatory reaction and minimal wound contraction were observed. Application of a split-skin mesh graft, in combination with this collagen matrix, generated a thicker dermal layer than did a split-skin mesh graft directly applied on a wound bed. However, the histologic dermal architecture was less optimal than one obtained with a full-thickness punch graft method. Other matrixes caused inflammatory reactions, interfering with epithelization and dermal reconstitution. We conclude that a nondenatured collagen matrix, in combination with a split-skin mesh graft, can provide a substitute dermis in a full-thickness wound. This combination is preferable to a split-skin mesh graft directly applied on the wound bed. With our microporous semipermeable membrane, the combined use of a dermal substitute and a split-skin mesh graft can be applied in a single-stage operation.