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Introduction: Seroma formation represents one of the most frequent postoperative complications of axillary dissection in breast cancer (BC) patients. We aimed to retrospectively explore the effectiveness of the intraoperative use of a synthetic cyanoacrylate glue (specifically Glubran®2) vs. the intraoperative use of a fibrin sealant (specifically Tisseel) in reducing seroma formation compared to the use of nonsealant in BC patients who underwent breast surgery and axillary dissection.Materials and Methods: We conducted a retrospective, monocentric observational study on BC patients who underwent axillary dissection associated with breast surgery. The axillary dissection was completed with the application of a closed suction drain and was preceded by the application of either Glubran®2 glue or Tisseel sealant or nonsealant. We analyzed the quantity of serum drained in the first 3 postoperative days, length of hospitalization, days of permanence of axillary drain, seroma development, and presence of postoperative infection signs.Results: Forty-one BC patients were considered. Based on the device used during the surgical treatment, the patients were divided into three groups: group A (17 patients), to whom suction axillary drain was applied; group B (7 patients), to whom Tisseel and axillary suction drain were applied; and group C (17 patients), to whom Glubran®2 and axillary suction drain were applied. Among the three groups, we did not find significant differences in terms of amount of serum drained in the first 3 postoperative days, length of hospitalization, and incidence of seroma. Group C maintained the axillary drain in a significantly lower number of days compared to the other two groups (p = 0.02); it also had a lower incidence of postoperative infections (6%) compared to group A (23%) and group B (57%) (p = 0.02).Conclusions: We did not find any evidence that the use of surgical glues may reduce the formation of seroma following axillary dissection in BC patients. Nevertheless, the use of cyanoacrylate glue in association with closed suction axillary drain seems to contribute to the reduction in days of axillary drain permanence and of postoperative infections, which are known factors delaying the schedule of any adjuvant oncological therapies.