The reconstruction of the foreskin using autografts is a complex procedure. A novel decellularisation method for epithelial tissue has been developed, producing an extracellular matrix scaffold from human donor foreskin. This study evaluated the immune response and integration of this scaffold after implantation in rats, focusing on inflammatory infiltrate, neovascularization, recellularization, and foreign body reaction. Twenty-six rats underwent a 1 cm infrascapular incision with scaffold implantation in the hypodermal layer. Group A (13 rats) was subject to a 30-day follow-up period, while Group B (13 rats) was subject to a 5-day follow-up period. Inflammation at the implantation site was scored from 0 (none) to 3 (severe). Tissue explants were. After 5 days (Group B) and 30 days (Group A), a tissue explant was performed and examined histologically and immunohistochemically. The clinical evaluation revealed slight signs of inflammation during the initial five days following the implantation procedure. Neutrophil (0.87 ± 0.35; 1 ± 0.53) and eosinophil (0.61 ± 0.51; 0.75 ± 0.46) presence was slight, with no significant differences between groups. Lymphocyte infiltration was moderate (1.87 ± 0.35; 1.75 ± 0.46), exceeding macrophage presence (1.25 ± 0.46; 1.12 ± 0.35). Neovascularization and cellular colonization were significantly greater at 30 days (2 ± 0.53; 2.42 ± 0.53) compared to 5 days (0.57 ± 0.21; 0.62 ± 0.32). Encapsulation remained mild in all cases, with no intergroup differences (0.87 ± 0.35). These findings indicate that the decellularized extracellular matrix derived from human foreskin elicits minimal immune response while promoting neovascularization and cellular repopulation. This supports its potential use as a biocompatible scaffold in reconstructive procedures.