Purpose: Evaluate the efficacy and safety of topical ciprofloxacin 0.3% plus fluocinolone acetonide 0.025% otic solution (CIPRO+FLUO) relative to ciprofloxacin 0.3% (CIPRO) alone, and to fluocinolone acetonide 0.025% alone in children with Acute Otitis Media with Tympanostomy Tubes Otorrhea (AOMT). Methods: This trial was conducted at multiple sites and was approved by the FDA and respective IRBs. 662 patients between 6 months and 12 years old with AOMT in at least one ear were enrolled. All patients were randomized and assigned to one of the 3 cohorts in a 1:1:1 ratio to receive CIPRO+FLUO, CIPRO alone or FLUO alone treatment for 7 days. Patients were monitored for compliance and presence of otorrhea using diaries and office visits. Middle ear exudate was submitted for a microbiological evaluation at visits 1, and 3 and 4 if present. The primary efficacy parameter was the time to cessation of otorrhea, defined as the first day on which otorrhea was absent and remained absent until the completion of the study. The secondary efficacy parameters included assessment of volume, color, consistency and viscosity of otorrhea, degree of pain, condition of the ear canal and the TM, presence of granulation tissue, and status of the PE tube. Clinical success was defined as complete resolution of clinical signs present at baseline. Clinical failure was defined as worsening, lack of change, or minimal improvement. Sustained microbiological cure was defined as eradication of pathogenic bacteria at both visits 3 and 4. Safety was assessed by the incidence of adverse events related to the study medication. Audiograms performed at visits 1 and 4 were compared. Statistical analyses were performed using SAS v9.3 software. Results: 662 children were enrolled. The median age was 2.51 years, 59.1% were male. The median time to cessation of otorrhea in patients receiving CIPRO+FLUO was 4.23 days (95%CI: 3.65-4.95), as compared with 6.95 days (95%CI: 5.66-8.20) in those receiving CIPRO alone (p < 0.001). In the FLUO group the number of patients with otorrhea was greater than the number of patients with cessation of otorrhea. The clinical cure rate at visit 4 was 80.6% in CIPRO+FLUO group, 67.4% (p=0.002) in CIPRO, and 47.6% (p < 0.001) in FLUO alone groups. Sustained microbiological cure was noted in 79.7% in the CIPRO+FLUO group vs 67.7% and 37.6%, in the CIPRO and the FLUO groups. Analyses of adverse events (AE) demonstrated that 3.1% of CIPRO+FLUO, 3.6% of CIPRO, and 4.7% of FLUO patients reported at least one AE related to the study medication. Conclusion: The combination of CIPRO 0.3% and FLUO 0.025% for 7 days is more effective than treatment with either CIPRO or FLUO alone for AOMT. It is safe, effective and is well tolerated in children.