Background: Polyurethane film dressings are commonly applied for coverage of split-thickness skin graft donor sites, although previous studies have suggested reduced morbidity using a polylactic acid membrane. To further investigate the optimal treatment approach, the authors compared outcomes of donor sites in patients receiving either polylactic acid membrane or polyurethane film. Methods: This randomized clinical trial allocated patients requiring split-thickness skin grafting to receive either polylactic acid membrane or polyurethane film at the donor site. The primary endpoint was difference in donor-site scar appearance between groups 3 months postoperatively, using the Vancouver Scar Scale. Secondary endpoints included pain, number of and time required for wound dressing changes, and costs related to the wound dressing. Results: Thirty patients were allocated to each group. The median Vancouver Scar Scale score was lower for patients receiving polylactic acid membrane [polyurethane film, 3 (interquartile range, 2 to 4); polylactic acid membrane, 2 (interquartile range, 1 to 3); p = 0.049]. Pain during change of wound dressing (polyurethane film, 2.0 ± 0.2; polylactic acid membrane, 0.5 ± 0.2; p < 0.001) and mobilization (polyurethane film, 0.8 ± 0.2; polylactic acid membrane, 0.3 ± 0.1; p = 0.032) were reduced in the polylactic acid membrane group. Patients with polylactic acid membrane required fewer dressing changes per day of hospital stay (polyurethane film, 0.44 ± 0.06; polylactic acid membrane, 0.28 ± 0.02; p = 0.015). Mean time for wound dressing changes per patient was higher in the polyurethane film group (polyurethane film, 74.50 ± 5.72 minutes; polylactic acid membrane, 21.43 ± 2.61 minutes; p < 0.001). Costs were higher in the polylactic acid membrane group (polyurethane film, €67.83 ± €5.56; polylactic acid membrane, €162.79 ± €21.76; p < 0.001). Conclusion: Polylactic acid membrane improves outcome of split-thickness skin grafting donor sites; however, higher treatment costs must be taken into consideration. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.