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Introduction: Various pain management strategies for patients undergoing open excisional hemorrhoidectomy have been proposed, yet postoperative pain remains a frequent complaint., Objective: To determine whether mesoglycan (30 mg two vials i.m. once/day for the first 5 days postoperative, followed by 50 mg 1 oral tablet twice/day for 30 days) would reduce the edema of the mucocutaneous bridges and thus improve postoperative pain symptoms., Patients and Methods: For this prospective observational multicenter study, 101 patients undergoing excisional diathermy hemorrhoidectomy for III-IV degree hemorrhoidal disease were enrolled at 5 colorectal referral centers. Patients were assigned to receive either mesoglycan (study group SG) or a recommended oral dose of ketorolac tromethamine of 10 mg every 4-6 hours, not exceeding 40 mg per day and not exceeding 5 postoperative days according to the indications for short-term management of moderate/severe acute postoperative pain, plus stool softeners (control group CG)., Results: Postoperative thrombosis (SG 1/48 versus CG 5/45) ( p < 0.001) and pain after rectal examination ( p < 0.001) were significantly reduced at 7-10 days after surgery in the mesoglycan-treated group, permitting a faster return to work ( p < 0.001); however, in the same group, the incidence of postoperative bleeding, considered relevant when needing a readmission or an unexpected outpatient visit, was higher, possibly owing to the drug's antithrombotic properties., Conclusions: The administration of mesoglycan after an open diathermy excisional hemorrhoidectomy can reduce postoperative thrombosis and pain at 7-10 days after surgery, permitting a faster return to normal activities.