Objective: Hyalomatrix, a matrix that consists of esterified hyaluronic acid, covered with a removable, semipermeable silicone top layer, was used to generate granulation tissue in a series of 12 serious, surgical wounds of different etiologies. Methods: Many defects showed exposed muscle, tendons, and/or bone. After thorough debridement, the matrix was applied, in a number of cases, combined with negative pressure wound therapy. Results: All wounds developed granulation tissue in and on top of the matrix. Nine wounds were then closed with a split skin autograft. There was no graft failure, and all wounds showed complete reepithelialization. Three wounds healed by secondary intention and also reached complete healing. Conclusion: This case series shows a strong trend for Hyalomatrix to play an important role in supporting wound healing in complex, surgical wounds.