Introduction. Graft fixation is critical for the successful survival of a skin graft. Conventional mechanical fixation may induce inappropriate pressure and increase wound complications. Negative pressure wound therapy (NPWT) could be utilized to secure a skin graft and improve drainage. Limited quantitative data exist on the efficacy of NPWT for skin grafting. Objective. This retrospective study compares the efficacy and complications between NPWT and conventional mechanical fixation in skin grafts. Materials and Methods. Patients who underwent skin graft surgery from January 2015 to December 2016 at a large university hospital in southwest China were retrospectively analyzed. Characteristics, including wound pattern, skin graft type, surgical procedure, survival rate, and postoperative complication, were statistically analyzed by Pearson chi-square or Fisher’s exact test. Results. A total of 186 patients were included in the study; 72 received NPWT and 114 received conventional mechanical dressing fixation after skin grafting. Overall survival rate of full-thickness skin grafts was significantly higher in the NPWT group than the dressing group (P < .01). The NPWT group showed a higher survival rate than the dressing group for each anatomic site, but only patients who had skin grafts of the hand exhibited statistically significant results. Conclusions. This study reports a quantitative analysis of the efficacy of NPWT on skin graft fixation with NPWT providing consistent pressure and better drainage than conventional mechanical fixation. In addition, the use of NPWT also could increase graft take on the hand region.