Background: Many patients with upper-abdominal malignancies suffer from severe lower back pain radiating to the epigastrium, caused by infiltration of the celiac plexus. The celiac plexus is a network of nociceptive nerves, located along the aorta. Contemporary approaches (opioids, celiac plexus chemical neurolysis, systemic chemotherapy) are often inadequate. The celiac plexus has not previously been targeted using radiation. We hypothesized that ablative radiation targeted to the celiac plexus would alleviate pain. Methods: We conducted a single arm prospective clinical trial. Eligible patients had celiac-pain > 4/10 on Numerical Rating Scale (NRS), ECOG ≤ 3, no previous abdominal RT, and were evaluable if they completed treatment per protocol with at least one post-treatment visit. The celiac plexus was irradiated from D12 to L2. Radiation was given as either five fractions of 9 Gy or a single-fraction 25 Gy. The primary endpoint was NRS pain 3 weeks post-treatment. Secondary endpoints were toxicity, pain at 6w, analgesic use, and pain interference with daily activities as evaluated by ‘Brief Pain Inventory’ before and after radiation. Results: 21 patients were evaluable: 2 received fractionated treatment, 19 received 25Gy single fraction. The median age of the study population was 63 yr with a median ECOG of 1, 86% had pancreatic cancer. Patients were a median of 8 months out from diagnosis, and had received a median of one systemic treatment. Toxicity was limited to grade 1-2. All patients reported decreased celiac pain: median baseline pain was 6/10 (IQR 5-7.7), was reduced to 2.3/10 (IQR 0.9-3.9) (p < 0.0005) at 3w, and to 1.8/10 (IQR 0-3.2) (p < 0.0005) at 6w post-treatment. Seven patients reported their celiac pain had been eliminated entirely. Median morphine consumption decreased (NS). Improvement was seen in multiple quality of life measures, includ. total wellbeing (p = 0.0001), daily activity (p = 0.005) and sleep quality (p = 0.002). Conclusions: Celiac plexus radiosurgery alleviates pain, and improves quality of life among patients with advanced upper-GI cancer. An international multi-center phase II trial is accruing. Clinical trial information: NCT02356406