Hydrogel dressings are gaining increased clinical acceptance as a wound management modality. The purpose of this study was to compare the effect of three amorphous hydrogels with occlusive, control treatment (Tegaderm) on healing of experimental wounds. Eight partial-thickness cutaneous wounds (2.5 cm x 2.5 cm x 0.04 cm) were made, using an electrokeratome, and the four treatments were allocated by randomisation within a cephalad and a caudal region on each of six 60-kg domestic pigs. In total, twelve wounds were each treated with 2.0 ml of each type of hydrogel--an experimental amorphous hydrogel ("Exgel"), IntraSite Gel and a poloxamer gel containing 3% hydrogen peroxide--and covered with Tegaderm, or treated with Tegaderm alone. At 66 h post-operatively, formalin-fixed, paraffin-embedded sections of wounds were hematoxylin-eosin-stained and assessed morphometrically for epithelium coverage in a blinded fashion. The Exgel remained macroscopically intact on the wounds in contrast to the other hydrogels, which had dissolved completely after treatment. Exgel significantly (p < 0.05) increased epithelial coverage of the wounds, compared with the other treatments (by 20% more than Tegaderm-treated wounds). In vitro experiments indicated that the polymeric matrix of Exgel sequesters bioactive molecules present in wound fluid and that it may in vivo act as a protective reservoir that delivers bioactive molecules at a rate that promotes epithelial migration. Exgel may represent a new treatment principle to promote wound healing.