In recent years the acellular dermal matrix (ADM) has gained popularity in prosthetic breast reconstruction. These procedures involve placement of a closed suction drain in the reconstructed breast. Although it is now widely accepted that ADM has an overall positive effect on the outcome of breast reconstruction, data regarding its effect on postoperative drain secretions is lacking. This study was designed to quantitatively evaluate the influence of ADM on postoperative drain secretions in the setting of immediate prosthetic breast reconstruction (IPBR). This is a prospective, comparative controlled study. Two groups of 16 patients each underwent skin sparing mastectomies (SSM) and IPBR with or without ADM. Closed suction drains were left in all the reconstructed breasts and daily secretion volumes were recorded and compared. Postoperative complications were also noted. Patients in the ADM group showed higher daily and overall secretion volumes compared with patients in the control group (p = 0.014) and the time for removal of the drains was higher by an average of 5 days (13 compared with 8 days, respectively; p = 0.004). There was no correlation between ADM and infection. This study provides the first objective evidence that ADM contributes to elevated and prolonged drain secretions when used for IPBR. This might affect possible prosthesis-related complications (e.g., rotation and malposition, capsular contraction, seroma formation, and infection). This study also noted erythema of the post-mastectomy skin flaps in selected patients, which may be attributable to a local inflammatory reaction to the ADM rather than infection.