Introduction Current efficacy data supporting the routine use of acellular dermal matrices (ADM) in postmastectomy tissue expander/implant reconstruction is limited. A multi-center, blinded, randomized controlled study was designed to evaluate the effectiveness of ADM in the setting of TE/I reconstruction. The primary objective of the study was to determine whether the use of ADM would decrease patient-reported, post-operative pain. The secondary objective was to determine whether the use of ADM accelerated the rate of post-operative expansion. Tertiary objectives included an evaluation of long-term aesthetic results, capsular contracture rates and patient satisfaction. Methods The randomized controlled trial was conducted at two centers in the US from 2008 to 2011. Immediately following mastectomy, all patients were randomized to one of two treatment arms: i) ADM-assisted, TE/I reconstruction and ii) placement of an expander in a completely submuscular position. All patients were blinded to their treatment arm. Results 108 consented to participate, 38 of whom were excluded prior to randomization. Thus, in total, 70 patients were randomized. There were no differences between the two groups in pain in the immediate, post-operative period (p=0.19) and pain averaged during the expansion phase (p=0.65). There was similarly no difference in post-operative narcotic use between treatment arms (p=0.38). The rate of post-operative expansion did not differ between groups (p= 0.83). The evaluation of long-term outcomes is currently ongoing. Conclusions The results of this multicenter, blinded, randomized controlled trial suggest that the use of ADM in the setting of TE/I reconstruction neither reduces post-operative pain nor accelerates the rate of post-operative expansion. This data provides impartial evidence on the effectiveness of ADM in the early post-operative period. An examination of the efficacy of ADM in improving long-term outcomes following TE/I reconstruction is warranted.