Ciprofloxacin 0.3%/dexamethasone 0.1% (CIP/DEX) and neomycin 0.35%(polymyxin B 10,000 IU/mL/hydrocortisone 1.0% (NPH) were compared for relief of pain in patients with acute otitis externa. Patients received 7 d of treatment with CIP/DEX twice daily or NPH 3 times daily. Ear pain was assessed by patients/caregivers twice daily and by the study investigator on days 3, 8, and 18 (4-point scale). Higher percentages of CIP/DEX-treated patients had relief of severe pain over time (P=.0013) and relief of significant pain (moderate or severe pain) over time (P=.0456), compared with NPH-treated patients. The percentage of CIP/DEXtreated patients with severe pain decreased rapidly within the first 12 h; this contrasted with an increase in pain among NPH-treated patients. CIP/DEX-treated patients had significantly less inflammation (P=.0043) and edema (P=.0148) than NPH-treated patients. Overall, these results support greater pain relief attained over the first 3 d in patients with acute otitis externa treated with CIP/DEX compared with NPH and a rapid reduction in severe pain after initiation of treatment.