Background: An acellular dermal matrix will typically incorporate, in time, with the overlying mastectomy skin flap. This remodeling process may be adversely impacted in patients who require chemotherapy and radiation, which influence neovascularization and cellular proliferation. Methods: Multiple biopsy specimens were procured from 86 women (n = 94 breasts) undergoing exchange of a tissue expander for a breast implant. These were divided by biopsy location: submuscular capsule (control) as well as superiorly, centrally, and inferiorly along the paramedian acellular dermis. Specimens were assessed for cellular infiltration, cell type, fibrous encapsulation, scaffold degradation, extracellular matrix deposition, neovascularization, mean composite remodeling score, and type I and III collagen. Patients were compared based on five oncologic treatment groups: no adjuvant therapy (untreated), neoadjuvant chemotherapy with or without radiation, and chemotherapy with or without radiation. Results: Biopsy specimens were procured 45 to 1805 days after implantation and demonstrated a significant reduction in type I collagen over time. Chemotherapy adversely impacted fibrous encapsulation (p = 0.03). Chemotherapy with or without radiation adversely impacted type I collagen (p = 0.02), cellular infiltration (p < 0.01), extracellular matrix deposition (p < 0.04), and neovascularization (p < 0.01). Radiation exacerbated the adverse impact of chemotherapy for several remodeling parameters. Neoadjuvant chemotherapy also caused a reduction in type I (p = 0.01) and III collagen (p = 0.05), extracellular matrix deposition (p = 0.03), and scaffold degradation (p = 0.02). Conclusion: Chemotherapy and radiation therapy limit acellular dermal matrix remodeling.