Objectives The purpose of this study was to determine the efficacy and safety of contrast-enhanced ultrasound (CEUS)-guided celiac plexus neurolysis (CPN) in patients with upper abdominal cancer pain. Methods Thirty-five patients with upper abdominal cancers tortured by intractable upper abdominal pain underwent CEUS-guided CPN with ethanol. The pain alleviation and opioid intake were observed and evaluated during a 3-month follow-up after CPN. The dispersion of alcohol around the aorta was evaluated on 3D-CEUS. Complications were assessed during CPN and at follow-up. Results All of the 35 patients' CPN was successfully achieved. Pain relief was observed in 28 (80%), 20 (57.1%), 27 (77.1%), 20 (57.1%), and 10 (29.4%) patients immediately, 1 day, 1 month, 2 months, and 3 months after CPN, respectively. The agent dispersion around the aorta on CEUS images of 28 patients who showed pain relief was at least 90 degrees of the circumference around the aorta. The median duration of pain alleviation was 2.7 months (95% confidence interval [CI], 2.5-2.9). Less than half of the patients had minor complications including irritant pain at the puncture site (8 of 35; 22.9%), diarrhea (4 of 35; 11.4%), nausea and vomiting (3 of 35; 8.6%), and post-procedural hypotension (1 of 35; 2.9%). Conclusions CEUS-guided CPN is a safe and effective method to alleviate refractory upper abdominal pain in patients with upper abdominal cancers. CEUS image allows the visualization of puncture path and observation of drug dispersion. The pain relief is relevant to the dispersion of neurolytic agent around the aorta.