The advent of skin- and nipple-sparing mastectomy in conjunction with the use of human acellular dermal matrix to provide lower pole coverage has made direct-to-implant immediate breast reconstruction following mastectomy feasible. The purpose of this study was to evaluate long-term complications associated with this technique. All human acellular dermal matrix-assisted direct-to-implant immediate reconstructions performed over an 8-year period were included in this analysis. Patient charts were reviewed for type of mastectomy (oncologic or prophylactic), incision type, complications during follow-up, length of follow-up, rate and type of revision surgery in breasts without postoperative complications, contralateral procedures, and adjuvant radiotherapy. A total of 466 breasts (260 patients) were reconstructed; 68 percent were prophylactic and 32 percent were oncologic cases. Twenty-one breasts (4.5 percent) received radiotherapy. Mean implant size placed was 412.8 ± 24.7 cc (range, 150 to 600 cc). Mean follow-up was 28.9 ± 21.3 months (range, 0.3 to 97.7 months). The overall complication rate was 3.9 percent (implant loss, 1.3 percent; skin breakdown/necrosis, 1.1 percent; hematoma, 1.1 percent; human acellular dermal matrix exposure, 0.6 percent; capsular contracture, 0.4 percent; and infection, 0.2 percent). Type, incidence, and overall rate of complications did not differ significantly between prophylactic and oncologic breasts. Irradiated breasts had a fourfold higher rate of complications. In 354 breasts with more than 1 year of follow-up (mean, 36.7 ± 18.6 months; range, 12.1 to 97.7 months), there were no long-term complications. Human acellular dermal matrix-assisted direct-to-implant breast reconstruction following mastectomy is safe and reliable, with a low overall long-term complication rate. The low incidence of capsular contracture supports the growing body of evidence that human acellular dermal matrix mitigates capsular contracture.