Background <p>This study aimed to conduct the first randomized clinical trial on the use of fibrin glue in split-skin grafts for skin cancer. Fibrin glue is an accepted technique for affixing split-skin grafts. Evidence suggests that fibrin glue has greater effectiveness than sutures or staples, particularly in populations with more comorbidities.</p> Methods <p>This randomized controlled clinical trial was conducted at a regional center in Queensland, Australia across the only two major hospitals in the area. The primary outcome assessed was graft take 1&#xa0;month postoperatively. Pain with dressing changes and incidence of seroma, hematoma, and infection as well as operative time were assessed as secondary outcomes. Patients were recruited and randomized to either fibrin glue or staples and sutures for graft affixation. They were subsequently followed up at 1&#xa0;week and 1&#xa0;month for outcome assessment.</p> Results <p>The study recruited 100 patients, and 83 patients with 133 grafts were analyzed for outcomes. Fibrin glue increased graft take by 17.13% when the study controlled for other variables. However, this was not statistically significant (<i>p</i> = 0.058; confidence interval [CI] − 0.63 to 34.89). There was a statistically significant reduction in the odds of seroma (odds ratio [OR] 0.08; CI 0.01–0.50; <i>p</i> &lt; 0.01) and infection (OR 0.04; CI 0.00–0.33; <i>p</i> &lt; 0.01) at 1&#xa0;week.</p> Conclusions <p>Fibrin glue may be of benefit for patients at higher risk for graft failure and is likely to benefit patients at increased risk of seroma and infection.</p> <p><i>Trial registration ANZCTR</i>: ACTRN12618000484246.</p>