Background Endoscopic ablation of Barrett's esophagus (BE) is a treatment option for patients with high-grade dysplasia (HGD) and intramucosal carcinoma (IMCA). Objective To assess the safety and efficacy of a unique noncontact method of liquid nitrogen cryoablation as measured by histologic response rate and cancer-free survival. Design Single-center, nonrandomized cohort study. Setting Referral center, conducted between September 2005 and September 2008. Patients Patients with BE and HGD or IMCA who were deemed inoperable or who refused esophagectomy. Age, length of BE, and previous ablation were not exclusion criteria. Intervention Cryoablation every 6 weeks until endoscopic resolution. EMR was used for pathologic staging of nodular areas before cryoablation and focal residual areas during the follow-up period. Main Outcome Measurements Histologic response was defined by the worst pathology obtained at any level of the esophagus or gastric cardia in 1 of 3 categories: (1) incremental = absence of HGD and IMCA in all biopsy specimens, (2) partial = residual IMCA with absence of any dysplasia, and (3) complete = absence of any intestinal metaplasia or dysplasia. Results Thirty patients underwent ablation; 9 had undergone previous ablation or mucosectomy. Twenty-seven of 30 patients (90%) had downgrading of pathology stage after treatment. Elimination of cancer or downgrading of HGD at last follow-up was 68% for HGD and 80.0% for IMCA, with a median follow-up period of 12 months (25th percentile, 6; 75th percentile, 24). Minor adverse events included mild pain (n = 7), a low incidence of mild strictures (n = 3), and lip ulcer (n = 1). One major adverse event (perforation) in a patient with Marfan syndrome occurred with the prototype system. During follow-up, 3 of 6 patients with complete response had recurrence of dysplasia or cancer in the gastric cardia. Limitations A nonrandomized, single-center study with a heterogeneous cohort of patients. Conclusions Patients with BE and HGD or IMCA have a positive response to endoscopic cryotherapy at 1-year follow-up.