Objective: To evaluate the use of skin homograft in major burn patients as regard indications, percentage of taking, cosmetic outcome, cost, and complications. In addition to comparing various laboratory data and notice the incidence of systemic inflammatory response syndrome (SIRS) occurrence pre-and post-operatively. And detect the mortality rate among the patients managed with homograft. Background: Burn is a type of physical trauma to skin or tissue. It can be produced by heat, chemical products, cold, electricity, or radiation. Burn can lead to loss of skin, resulting in deep, widespread skin wounds or even death. Therefore, finding an appropriate skin substitute in such patients is one of the main concerns of clinicians. Method: This prospective comparative study was done at the department of plastic and reconstructive surgery, Menoufia University Hospitals, from December 2017 to July 2020. It was conducted on 31 patients with major burns; to evaluate the use of skin homograft in major burn patients regarding indications, the percentage of taking, the survival time, and the complications. Also, to detect the incidence of occurrence of systemic inflammatory response syndrome (SIRS) and the mortality rate among the patients managed with homograft. All studied patients and donors were subjected to take a full history, general and local examination, investigations as complete blood counts (CBC), blood glucose level, kidney and liver function tests, electrolytes, and coagulation profile. Preoperative preparation, intraoperative and postoperative care was done. Results: The study revealed that there was a highly significant decrease in postoperative temperature, heart rate, respiratory rate, systemic inflammatory response (SIRS) score, total leucocytic count (TLC), and K measurements in homograft patients (p < 0.05 respectively). Comparative study between pre-and post-operative measurements revealed; a highly significant increase in post-operative albumin and Na measurements in homograft patients (p < 0.05 respectively). Conclusion: The current work concluded that the use of homograft in major burn patients improved their overall condition by improving laboratory and respiratory data post-operatively. Furthermore, it reduces the raw area, reduces fluid and electrolyte loss, and rapid wound healing. Furthermore, we discovered a significant reduction in the SIRS score, reducing sepsis and improves morbidity and mortality.