Background: Ultrasound-guided percutaneous cryoablation of intraabdominal malignancy such as liver and kidney tumors, has been reported. To our knowledge, our group was the first to apply the cryotherapy with percutaneous approach to pancreatic cancer. Aim: To demonstrate feasibility, safety, and short-term outcome of percutaneous cryotherapy for advanced pancreatic cancer. Methods: Consecutive patients with advanced, non-resectable pancreatic cancer with vascular and lymph node involvement or liver metastasis underwent percutaneous cryotherapy at Fuda Hospital from Sept 2008 to Sept 2009 were included in the study. All patients had failed gemcitabine-based chemotherapy. Percutaneous cryotherapy was performed by argon/helium-based cryosurgical system (Endocare, CA, USA). Serum amylase evaluation was performed during preoperative assessment, 1 to 7 days postoperatively and again when the patient returned for follow up imaging. CT or PET-CT scanning was performed for evaluation of tumor response every 4 to 6 weeks after cryoablation. Results: There were a total of 59 patients (35 males and women 24 females) with a median age of 57 years (range 38 to 85). There were a total of 76 biopsy-proved tumors, located at the pancreas head (56), body (7) cases, and tail (13). The median size of tumor on CT scan was 4.5 cm (range 3-6). Nineteen patients had liver metastases. There was no death associated with cryothererapy. Minor adverse effects included transient abdominal pain in 45 cases (59.2%) and elevation of serum amylase in 34 (44.7%). Major morbidity was intra-abdominal bleeding in 2 cases (3.4%), pancreatic leaks, ileus, and metastasis of probe tract in 1 (1.7%). The median hospital stay was 21 days, and a median follow-up of 75 months (range 3 to 14). According to The Response Evaluation Criteria in Solid Tumors (RECIST) protocol, none of the patients achieved complete response in pancreatic cancer, 23 (38.8%) had partial response, 32 (54.2%) had stable disease, 4 (6.8%) had progressive disease. 19 cases (32.2%) developed liver or lung metastases during the followup. The overall survival at 3, 6 and 12 months was 89.7%, 61.1% and 34.5 %, respectively. Of 40 patients without liver metastases and 19 patients with liver metastases, 3-, 6-and 12month survival were 92.4%, 84.2%, and 62.1% and 59.3%, 43.2%, and 13.7%, respectively (P < 0.05). Conclusion: Ultrasound-guided percutaneous cryotherapy appears to be a safe and feasible, minimally invasive technique for pancreatic cancer. Short-term follow-up in our series is encouraging, although further studies with long-term follow-up are needed to access properly the value of this technique.