Background <p>Prepectoral breast reconstruction using acellular dermal matrices (ADMs) or micro-polyurethane foam-covered breast implants have emerged as commonly used surgical techniques. Although the use of both ADMs and micro-polyurethane foam-covered implants in prepectoral breast reconstruction are widely described in literature, comparative data remains limited.</p> Objectives <p>Our goal was to compare the short-term and medium-term clinical outcomes as well as the patient-reported outcomes in patients undergoing direct-to-implant (DTI) prepectoral breast reconstruction using ADM versus micro-polyurethane foam-covered implants.</p> Methods <p>A retrospective matched cohort study was conducted on 64 patients (32 ADM-wrapped and 32 micro-polyurethane foam-covered breast implants). Patients were matched based on prior surgery, adjuvant radiotherapy, and implant volume. Demographic and oncological characteristics, surgical variables, short- and medium-term outcomes, and patient-reported outcomes were compared between the two groups.</p> Results <p>The micro-polyurethane group had significantly older patients (median age 53 vs. 47 years; <i>p</i> = 0.036). Periprosthetic fluid collection (31% vs. 3%; <i>p </i>= 0.006) and need for percutaneous fluid aspiration (38% vs. 9%; <i>p </i>= 0.016) occurred significantly more often in the ADM group. The indication for further surgery was also higher with ADM (47% vs. 19%; <i>p </i>= 0.031). Patient satisfaction showed a non-significant trend favoring micro-polyurethane implants in satisfaction with outcome domain (mean: 89 vs. 82; <i>p </i>= 0.060).</p> Conclusions <p>Both ADM-assisted reconstructions and micro-polyurethane implants demonstrated high performance in the short and medium term, and they were associated to high patient satisfaction with reconstruction. However, micro-polyurethane implants were associated with fewer periprosthetic fluid collections and a lower need for percutaneous fluid aspirations compared to the ADM group. These findings suggest a potential advantage in terms of reduced postoperative complications.</p> Level of Evidence III <p>This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors <a href="http://www.springer.com/00266">www.springer.com/00266</a>.</p>