Reconstructive surgery with synthetic or biological materials is commonly performed to repair abdominal wall musculofascial defects that result from ventral hernias. A study was conducted to investigate the feasibility of using silk fibroin and chitosan blend (SFCS) scaffolds for ventral hernia repair in guinea pigs. We compared SFCS with biodegradable human acellular dermal matrix (HADM) and nonbiodegradable polypropylene mesh by implanting each to repair an incisionally created ventral hernia in the abdominal wall using an inlay technique. At 4 weeks, both HADM and SFCS underwent remodeling by host tissue, but polypropylene mesh resulted in extensive bowel adhesions and scarring. Abdominal wall repairs with SFCS showed tissue remodeling in all 3 dimensions, with seamless integration at the interface with adjacent native tissue. The SFCS repair sites remained intact, and their mechanical strength was similar to that of the native abdominal wall despite greater degradation and remodeling of SFCS than of HADM. The deposition of new extracellular matrix consisting of collagen and ground substance, uniform vascularization, and cellular infiltration in SFCS repair sites contributed to the increase in mechanical strength of the regenerated tissue. Thus, SFCS is a potentially useful material for clinical abdominal wall reconstruction, since it becomes remodeled and integrated into the surrounding abdominal wall and maintains adequate tensile strength.