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Background and Objectives: The most common complication of tympanostomy tube (T-tube) insertion is the development of postoperative otorrhea. Post-tympanostomy tube otorrhea (PTTO) is defined as active drainage through an existing T-tube. Many surgeons routinely use topical antibiotics as prophylaxis against early PTTO. Mupirocin calcium ointment is a topical antimicrobial agent with broad-spectrum antimicrobial activity against many Gram-positive organisms. This study evaluated the clinical effectiveness of topical mupirocin ointment in reducing early PTTO. Subjects and Methods: The study included 98 ears (67 patients, mean age 32.9 years) that had a T-tube inserted because of chronic middle ear effusion or atelectatic otitis media. A Paparella type-I polyethylene-tube coated with mupirocin was inserted through the tympanostomy. Patients were instructed not to use otic drops or any other medications. All patients were seen by day 14 postoperatively. Results: Early PTTO occurred in one case (1.5%). No early PTTO was seen with a middle ear effusion. Nineteen children were treated under general anesthesia; none developed early PTTO. Conclusions: Insertion of a T-tube coated with mupirocin ointment could be effective at preventing early PTTO.