OBJECTIVE To analyze the efficacy of Ciprodex otic augmented with N-acetylcysteine (NAC) against difficult ear infections. METHODS Subjects were selected with at least 1 month of continuous otorrhea despite at least 3 distinct medical or surgical treatments. METHODS Subjects received Ciprodex otic augmented with 0.5 or 2% NAC using standard dosing schemes. METHODS Serial audiometry and cessation of otorrhea by both history and binocular microscopy. RESULTS Seven subjects were included with an average of 18.4 months of continuous otorrhea despite aggressive therapy. Cessation of otorrhea was achieved in 6 of 7 subjects generally within 4 weeks of treatment. One of these 6 subjects remains on chronic suppressive therapy. The remaining subject failed because of persistent noncompliance. No subjects demonstrated ototoxicity via pretreatment and posttreatment audiometry. CONCLUSIONS Ciprodex otic augmented with NAC seems to have considerable efficacy against otherwise refractory ear infections. This technique may prove to be a simple and powerful option for the treatment of difficult ear infections.