Objective: Pre-pectoral reconstruction after nipple-sparing mastectomy (NSM) avoids animation deformity and is associated with less morbidity. Traditionally, NSM poses an increased risk of nipple ischemia and potential implant contamination through the remaining nipple ducts. Therefore, it appears of importance that a “barrier” between the prosthesis and the outside world be preserved. In subglandular prosthetic reconstruction, acellular dermal matrix (ADM) has been used with success but also linked with increased complications. This study compared surgical outcomes of implant-based pre-pectoral reconstruction after NSM with and without ADM. Methods: All patients who underwent immediate breast reconstruction with pre-pectoral tissue expander (TE) or direct-to-implant (DTI) after NSM by the senior author between April 2013 to January 2021, were included in this study. Cohorts were stratified into breasts with ADM or without ADM. DTI and TE groups were also analyzed irrespective of ADM use. Complications within 30 days were analyzed. Minor complications included erythema, seroma, flap necrosis, nipple necrosis, and prescription of extra antibiotics. Major complications included hematoma, dehiscence, infection, hospitalization, necrosis requiring surgery, any surgical intervention, capsular contracture, and implant loss. Ecchymosis was individually measured. Results: A total of 115 pre-pectoral reconstructions were performed in 66 patients, including 80 TE and 35 DTI placements. The mean patient age was 48 ± 11 years and BMI 27 ± 5.3. Groups appeared uniform with regards to patient demographics. Major complications occurred in 65 (56.5%) of reconstructed breasts, with necrosis requiring excision being the most common complication (24/65, 37%). Smokers experienced 3.1 times more major complications (p<0.012) and required 4.5 times more post-operative antibiotics (p<0.01) irrespective of ADM use or implant type. There were 75 breasts with ADM and 40 breasts with no ADM. ADM breasts had higher rates of ecchymoses (70.7% vs 30%, p<0.001) and nipple necrosis (28% vs 10%, p=0.026). ADM use was also associated with less capsular contracture (16% vs 37.5%, p<0.01) at latest follow-up 577 ± 453 days. Interestingly, although DTI volumes were greater than initial TE fill volumes (473±88 ml vs 229±130 ml, p<0.0001), DTI was associated with lower rates if major complications (37.14% vs 65%, p<0.005), including loss of implant (5.7% vs 38.75%, p<0.001) or any complication necessitating surgery (14.3% vs 27.5%, p=0.024). Conclusion: ADM use in pre-pectoral implant-based breast reconstruction after NSM increases the likelihood of ecchymoses, mastectomy flap necrosis and nipple necrosis, but appears protective against capsular contracture, which could be due to its properties as a subareolar barrier. As compared to DTI, TE placement led to more complications possibly due to suspected intra-operative flap ischemia that likely influenced device choice. Intra-operative perfusion mapping should be employed to identify ischemia and increase success of prosthetic reconstruction. In smokers, prosthetic reconstruction after NSM leads to exceptionally high complication rates and should be offered with caution. Corresponding Author: Elizabeth Bushong, 15 Michigan St NE, Grand Rapids, MI 49503, [email protected], (760) 285-4085