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Up to 90% of patients undergoing breast cancer surgery suffer from seroma formation, which can cause discomfort and various complications after mastectomy. This retrospective observational cohort study aimed to elucidate whether flap fixation with fibrin sealant (ARTISS) tissue glue reduces seroma formation and seroma aspiration after mastectomy when compared with flap fixation using Vicryl sutures and when compared with a conventional wound closure technique.All patients undergoing mastectomy due to invasive breast cancer or ductal carcinoma in situ were eligible for inclusion. From May 2012 to March 2013, all patients undergoing mastectomy in 2 large breast cancer centers were treated using flap fixation with Vicryl sutures. From September 2013 to March 2014, all patients undergoing mastectomy were treated with flap fixation using ARTISS tissue glue. The data were retrospectively analyzed and compared with a “drain-only” group that was not treated with flap fixation (May 2011-March 2012).A total of 230 women who underwent mastectomy were retrospectively analyzed in this trial; 88 patients were included in the drain-only group (DO), 92 patients were included in the flap fixation group using Vicryl sutures (FF-1), and 50 patients were included in the flap fixation group using ARTISS tissue glue (FF-2). There was significantly less seroma formation in the group after flap fixation using sutures (P = .006). There were significantly fewer patients who required seroma aspiration in the FF-1 group (P = .001) and the FF-2 group (P = .001) after undergoing mastectomy and sentinel node biopsy or modified radical mastectomy.This study suggests that flap fixation after mastectomy using ARTISS tissue glue or sutures reduces postoperative seroma aspiration. As a result, flap fixation might lead to less patient discomfort. A randomized, prospective trial should be performed to verify these results.Seroma formation and its sequelae cause complications and discomfort following mastectomy. In this retrospective study of 230 patients, patients underwent flap fixation after mastectomy using sutures or tissue glue. The results were compared to a group that had not been treated with flap fixation. The occurrence of seroma was significantly less in the group undergoing flap fixation with sutures. There were significantly fewer patients requiring seroma aspiration in both groups undergoing flap fixation.