Staged, tissue expander-based implant reconstruction continues to be the most common mode of breast reconstruction after mastectomy and has evolved significantly for the past 60 years. Prepectoral acellular dermal matrix (ADM)-assisted breast reconstruction is gaining popularity with complication rates similar to total submuscular and ADM-assisted partially submuscular reconstruction. Ours is among the first reports comparing postoperative pain and early functional outcomes between 2-stage ADM-assisted prepectoral and partial submuscular breast reconstruction. Patients reconstructed with a 2-stage, ADM-assisted prepectoral approach were case matched with patients who had undergone ADM-assisted, partial submuscular reconstruction. Demographics and complication rates were compared. Primary outcomes included postoperative pain, number of days until full active shoulder range of motion was achieved, and postoperative days until drain removal. Forty-five breasts among 24 patients were reconstructed with ADM-assisted prepectoral tissue expanders after mastectomy and 90 breasts among 48 patients were reconstructed with ADM-assisted partial submuscular placement. There was a similarly acceptable complication profile between the 2 groups. The prepectoral group had significantly lower inpatient pain scores, required significantly less intravenous opioids and less oral opioids as outpatients. The prepectoral group saw a return to full active range of shoulder motion in half the number days of the partial submuscular group. Drain duration was similar between groups. Prepectoral ADM-assisted breast reconstruction can be performed safely and with significantly less pain and earlier return to function than partial submuscular expander placement. Expander placement exclusively in the prepectoral pocket did not result in increased drain duration while affording patients the benefits of avoiding surgical elevation of the pectoralis muscle.