Seroma formation is a common postoperative complication in plastic surgery, resulting in notable patient morbidity and expense. In this study the authors investigated the efficacy of a synthetic glutaraldehyde-based tissue adhesive (BioGlue; Cryolife, Inc., Kennesaw, GA) in seroma prevention in the rat mastectomy seroma model. This tissue adhesive is composed of purified bovine serum albumin (45%) and glutaraldehyde (10%). Twenty-two Sprague-Dawley rats received mastectomies along with axillary lymphadenectomy and disruption of subcutaneous lymphatics. The control group (N = 11) received 2.5 ml saline into the wound before closure. In the experimental group (N = 11), 2.5 ml BioGlue was injected into the wound. On postoperative day 7, the resultant seromas were quantified and adjacent tissues were harvested for histological examination. The rats in the control group had a mean seroma volume of 5.19 ml (standard deviation, +/- 3.65 ml; N = 11), whereas the rats treated with BioGlue had a mean seroma volume of 0.25 +/- 0.43 ml (N = 11). Histology revealed an inflammatory response consistent with postoperative changes as well as a mild foreign body reaction. This study demonstrates that BioGlue can be used as a tissue adhesive that reduces seroma formation significantly in the rat mastectomy model (p = 0.0008). Further studies are warranted to investigate the long-term effect of BioGlue on surrounding tissue.