Background: Patients with locally advanced esophageal cancer can have progressive dysphagia and associated worsening quality of life (QOL). Maintenance of esophageal patency by reducing intraluminal tumor burden can improve QOL by palliating dysphagia and delay or prevent the need for feeding tubes and esophageal stents. We aimed to assess the effect of endoscopic palliative cryoablation with trūFreeze Spray Cryotherapy (SCT) on dysphagia burden, QOL, and survival in patients with esophageal cancer. Methods: This is a multi-center prospective study of esophageal cancer patients at 10 sites in the United States. Subjects are 18-89 years old with luminal esophageal cancer, non-surgical candidates, not receiving systemic therapy, without esophageal stents, or history of prior SCT for esophageal cancer. SCT is an endoluminal ablation modality using non-contact medical grade liquid nitrogen (LN2) reaching a temperature of -196⁰ C delivered by a catheter. SCT was performed at 6 week intervals or as clinically indicated at a dose of 2x30 or 3x30 seconds per every 2-3 cm treatment site. Dysphagia and QOL were assessed with the 5-point Dysphagia score and EORTC QLQ 30 and OES18 esophageal module. Results: Of 49 subjects, mean age is 74.2 ± 11.8, 88% are men, 92% have esophageal adenocarcinoma and 19% have prior esophageal surgery or esophagectomy. 75% had a history of chemotherapy and/or radiation, and 58% (n=21) had a tumor stage >2. Subjects had a total of 258 treatment sessions over a mean follow-up of 329.7 ± 219.1 days, and received a median of 4 (IQR:2-7) SCT sessions with an average dose of 90 (3x30 sec) seconds/treatment site. There were 19 procedure related adverse events (20.4% of patients and 7.4% of procedures), all of which were mild (n=13) or moderate (n=6) in severity. Mean baseline dysphagia score was 1.7 ± 0.9 and 89% maintained (72%) or improved (17%) their baseline dysphagia score after initial SCT, p<0.05, and maintained this degree of symptom burden with ongoing SCT for a mean 239 ± 198 days. 28.6% (n=14) needed an esophageal stent after a mean 168 ± 169 days and 8% (n=4) had a feeding tube placed after a mean 145 ± 76 days after initial treatment. There was improvement in global health status (61.9 ± 23.3 vs 67.7 ± 19.7) and social functioning (73.9 ± 24.7 vs 81.2 ± 28.0) with decreased dysphagia (OES18: 21.5 vs. 16.7) and eating problems (26.1 vs. 20.6), p<0.05 for all. During the follow-up period, 49% of this palliative group survived and median survival was 386 days. Factors associated with survival with SCT were earlier cancer stage (69% stage 1 or 2 were survivors vs. 20% non-survivors; p=0.03) and ≤25% of luminal obstruction by tumor (62% vs. 36%; p=0.06). Conclusions: Liquid nitrogen SCT is an effective option to curb dysphagia progression in palliation of esophageal cancer and improves overall quality of life. Degree of luminal obstruction and tumor stage predicted survival. Clinical trial information: NCT03243734