One half to one third of the patients with eosinophilic esophagitis (EoE) do not achieve histological remission on initial treatment. We wondered whether these treatment failure patients are a distinct clinical subset. To analyze EoE treatment outcomes in a predominantly pediatric population. We reviewed 100 serial EoE cases at Massachusetts General Hospital starting from 2007. We defined histological remission as peak esophageal eosinophil count of less than 10/hpf. Ninety-seven patients with EoE underwent initial treatments: 54 of 81 (67%) responded to dietary therapy, and 9 of 16 (56%) responded to topical glucocorticoids. Of the 34 who failed initial treatment, 24 underwent various second treatment regimens and 54% (13 of 24) responded. Eight of the remaining 11 who failed second treatment underwent additional treatments and 2 ultimately responded. The overall response rate by intent-to-treat analysis increased from 65% (63 of 97) with initial treatment to 78% (76 of 97) with rescue treatment, and further to 80% (78 of 97) with multiple treatments. On a per-protocol basis, the overall response rate was 93% (78 of 84); however, patients who failed the first 2 rounds of therapy had only a 20% response rate. Patients who responded to initial treatment were found to have more symptoms and endoscopic abnormalities. Comparison of patients who failed both initial and rescue therapy with those who responded to rescue therapy did not identify any differentiating clinical features. More than half of the patients who failed initial EoE treatment could still achieve histological remission with individualized rescue treatments. No clinical features could predict response to rescue treatment.