Total skin-sparing mastectomy (TSSM) has become increasingly frequent in recent years, as inclusion criteria continue to expand. Options for tissue expander coverage in these patients include complete submuscular tissue expander coverage and acellular dermal matrix (ADM)-assisted coverage. This study compares both techniques with regard to relevant outcomes, during a recent 1-year period at our institution.All women undergoing TSSM and immediate expander placement between January 2012 and January 2013 were prospectively tracked. Patient demographics, expander coverage type, adjuvant treatment, length and characteristics of expansion, and incidence of complications were analyzed.In 1 year, 127 patients underwent TSSM on 202 breasts. Overall, 113 expanders underwent submuscular coverage, and 89 underwent ADM-assisted coverage. Mean intraoperative fill volume was 52 mL in the submuscular cohort and 205 mL in the ADM cohort (P = 0.0001). Mean tissue expander size was 404 mL in the submuscular cohort and 454 mL in the ADM cohort (P = 0.0002). χ analysis demonstrated no differences between the cohorts in incidence of complications, including partial/complete nipple necrosis.The use of ADM for expander coverage after TSSM allowed for greater initial expander fill. With large and ptotic breasts, this allows for reduced incidence of skin folds in the preserved breast skin pocket, and greater control over final nipple position, as the amount of loose, mobile skin is reduced by the greater initial fill. The safety profile of ADM use after TSSM is equivalent to that of submuscular coverage, with no differences in partial or complete nipple necrosis.