Purpose <p>Animal tissue, commonly used as a xenograft, is a significant source of scaffolds. However, it contains xenoantigens that could induce immune rejection. In this study, we employed antigen removal techniques to modulate both acute and chronic inflammatory responses in hosts using decellularized myocardial xenogeneic tissue.</p> Methods <p>We collected xenogeneic myocardial tissue samples from sheep and subjected them to a decellularization process using a solution containing 0.1% SDS and 0.01% trypsin applied through immersion. Following this, the samples underwent an antigen removal (AR) treatment, which included the addition of DTT, KCl, and MgCl₂. We established six groups for implantation: fresh samples, decellularized samples, and decellularized samples treated with AR. These samples were implanted in the subcutaneous tissue of mice for durations of 14&#xa0;days (acute phase) and 60&#xa0;days (chronic phase), with three groups for each duration. The implanted tissues were then processed into histological slides to study histopathology and the expression of inflammatory cytokines (IL-1β, IL-6, and IL-10).</p> Results <p>The results demonstrated that the AR technique effectively prolonged the degradation process of the scaffolds and reduced the infiltration of inflammatory cells and mast cells, as well as the expression of proinflammatory cytokines. The decellularized scaffolds remained intact up to 60&#xa0;days post-implantation.</p> Conclusion <p>This study concludes that AR treatment effectively modulates the immune response to implanted scaffolds in decellularized xenogeneic myocardium.</p> Lay Summary <p>Tissues of animal origin are an abundant source for scaffolding in tissue engineering; however, the presence of xeno-antigens presents a significant challenge, often causing acute and chronic rejection by the immune system. To address this, we employed decellularization and antigen removal techniques in this study. These methods successfully modulated the host immune response toward xenogeneic myocardial tissue. Our findings indicate that removing antigens post-decellularization is a promising strategy to slow the degradation process of xenogeneic scaffolds by up to 60&#xa0;days, primarily through the reduction of inflammatory cells and mast cells, along with controlled expression of inflammatory cytokines. This research contributes to the field by demonstrating that post-decellularization AR techniques can effectively modulate the immune response in engineered xenogeneic tissue.</p> Graphical Abstract <p></p>