BACKGROUND: Increasing amounts of acellular dermal matrix are being used with the adoption of prepectoral breast reconstruction. Postoperative infection remains a challenge in breast reconstruction, and the contribution of acellular dermal matrix type, processing, and sterility assurance level to risk of complications in prepectoral reconstruction is not well studied. METHODS: The authors performed a retrospective review of patients who underwent immediate prepectoral breast reconstruction from February of 2017 to July of 2020. Because of an increase in the rate of infection, the drain protocol was changed and acellular dermal matrix type was switched from AlloDerm (sterility assurance level, 10-3) to DermACELL (sterility assurance level, 10-6) in January of 2019. Demographic and surgical variables were collected, in addition to details regarding development and management of infection. RESULTS: Despite higher rates of direct-to-implant reconstruction and bilateral procedures and increased implant volumes, the rate of infection was significantly lower in patients who received DermACELL instead of AlloDerm [two of 38 (5.3 percent) versus 11 of 41 (26.8 percent); p = 0.014]. Drain duration was slightly longer in the DermACELL group, consistent with the change in drain protocol. Baseline demographic and clinical characteristics remained similar between the two groups. CONCLUSIONS: With increased reliance on large amounts of acellular dermal matrix for prepectoral breast reconstruction, it directly follows that the properties of acellular dermal matrix with respect to incorporation, sterility, and implant support are that much more important to consider. There have been few studies comparing different types of acellular dermal matrix in prepectoral breast reconstruction, and further research is required to determine the contribution of acellular dermal matrix type and processing techniques to development of postoperative infection. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.