Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease in which food antigens play a key role. Current therapeutic options are limited to long-term steroid medication and dietary elimination of multiple foods, each of which is challenging. Our objective was to compare single food elimination of cow's milk to swallowed fluticasone in pediatric EoE patients. This is a prospective, comparative effectiveness trial of newly diagnosed EoE patients (ages 2-18 years) treated with swallowed fluticasone (n = 24) or elimination of cow's milk (n = 20). The dual outcome measures of repeat esophageal biopsy (6-8 weeks) and change in Pediatric Quality of Life Inventor (PedsQL) EoE Module and Symptoms Scales were used to assess response to treatment. After 6-8 weeks of treatment, peak esophageal eosinophil counts decreased to below the threshold of 15 eosinophils/high-power field in 64% of patients treated with cow's milk elimination and 80% of patients treated with swallowed fluticasone (P = 0.4). Mean PedsQL EoE Module total scores (69 vs. 82; P < 0.005) and Total Symptoms scores (58 vs. 75; P = 0.001) showed significant improvement with cow's milk elimination. Among children treated with swallowed fluticasone, mean PedsQL EoE Module total scores (64 vs. 75; P < 0.05) and Total Symptoms scores (58 vs. 69; P < 0.01) were also significantly improved after 6-8 weeks of therapy. Removal of cow's milk from the diet is an effective single food elimination treatment for pediatric patients with EoE as assessed by statistically significant histologic and symptomatic improvement. Cow's milk elimination may be more desirable for EoE patients who do not want to take chronic, long-term steroid medications.