<b><i>Background:</i></b> Over the last decades, the number of acellular dermal matrix (ADM)-assisted implant-based breast reconstructions (IBBR) has substantially increased. However, there is still a lack of prospective data on complication rates. <b><i>Methods:</i></b> We performed a non-interventional, multicenter, prospective cohort study to evaluate complication rates of a human ADM in patients undergoing an IBBR after skin- and nipple-sparing mastectomies. Patients with primary reconstruction (cohort A) and patients undergoing a secondary reconstruction after capsular fibrosis (cohort B) using the human ADM Epiflex® (DIZG gGmbH, Berlin, Germany) were enrolled in this study. Patients were followed-up for 12 months after surgery. <b><i>Results:</i></b> Eighty-four eligible patients were included in this study of whom 28 women underwent a bilateral breast reconstruction, leading to 112 human ADM-assisted reconstructions in total (cohort A: 73, cohort B: 39). In 33.0% of the reconstructed breasts at least one of the complications of primary interest occurred, including implant loss 7.1%, seroma 15.2%; infection 5.4%, rash 8.0%, and Baker grade III/IV capsular fibrosis 2.7%, with no statistically significant differences between the cohorts. Previous radiation therapy was significantly associated with occurrence of any postoperative complication (OR 20.41; <i>p</i> value 0.027). <b><i>Conclusion:</i></b> The rates of most complications were comparable to the rates reported for other ADMs with relatively low rates of capsular fibrosis and infections. The rate of seroma was increased in our study. Prior radiation therapy increased the risk of any postoperative complications. Therefore, the use of ADM in these patients should be considered carefully.