ABSTRACT: Various materials and approaches have been used to optimize the biocompatibility of mesh to reduce the implant-induced host response in intraperitoneal onlay mesh (IPOM) repair. Ineffective host integration, limited resistance to contamination, and untargeted administration hinder the wider application of the currently available clinical options. In this study, human amniotic membrane (HAM) was decellularized, fully characterized, and compared with porcine small intestinal submucosa (SIS) in terms of its structure, components, and bioactivity. In an in vivo study, HAM was reinforced with silk fibroin (SF) membrane, which was fabricated as a biodegradable submicroscale template by electrospinning, to construct a bilayer composite mesh. The independent SF membrane, associated with HAM and SIS, was evaluated for tissue remodeling in vitro. The HAM-SF and SIS meshes were then characterized morphologically and implanted intraperitoneally into Sprague-Dawley rats for 28 days for macroscopic investigation of their integration into the host via interactions of regulatory factors. After decellularization, HAM formed a bioagent-rich collagen-based acellular structure. HAM was superior to SIS in concurrently suppressing the expression of transforming growth factor ?1 (TGF-?1) and proangiogenic proliferation. When HAM, SF, and SIS were used as regenerative scaffolds, they showed qualified biocompatibility, cell infiltration, and degradation in vitro. Comparatively, macroscopic observation after implantation indicated that HAM-SF induced less-intensive intraperitoneal adhesion and weaker inflammatory responses at the interface but greater angiogenesis in the explant than SIS. Analysis of the expression of regulatory factors showed a greater quantity of hepatocyte growth factor (HGF) in HAM, which partly inhibited the expression of TGF-?1 and promoted vascular endothelial growth factor (VEGF)-induced angiogenesis. This bioactive interaction appeared to be responsible for the better host integration, making HAM more biocompatible than SIS in IPOM repair. When combined with SF, HAM displayed similar mechanical properties to SIS. In conclusion, HAM displayed better bioactivity and biocompatibility than SIS. After its reinforcement with SF, HAM-SF is a promising biocomposite mesh for IPOM repair.