Immediate breast reconstruction has become a standard of care following mastectomy for cancer, largely due to improved esthetic and psychologic outcomes achieved with this technique. However, the current historical standards—transverse rectus abdominis myocutaneous flap reconstruction and expander-implant surgery—still have limitations as regards patient morbidity, short-term body-image improvements, and even cost. To address these shortcomings, we employ a novel concept of human tissue replacement to enhance breast shape and provide total coverage, enabling immediate mound reconstruction without the need for breast expansion prior to permanent implant placement. AlloDerm (human acellular tissue matrix) is a human-derived graft tissue with extensive experience in various settings of skin and soft tissue replacement surgery. This report describes the success using acellular tissue matrix to provide total coverage over the prosthesis in immediate reconstruction, with limited muscle dissection. In this population, 49 patients (76 breasts) successfully underwent the acellular tissue matrix-based immediate reconstruction, resulting in durable breast reconstruction with good symmetry. These findings may predict that acellular tissue matrix–supplemented immediate breast reconstruction will become a new technique for the immediate reconstruction of the postmastectomy breast.