Background and Objective: CybeKnife is a newly developed technology in the field of stereotactic radiosurgery/radiotherapy (SRS/SRT). Compared with conventional SRS/SRT, there are many advantages for CyberKnife in terms of treating tumors that move with respiration, being real-time image-guidance, frameless, high accurateness, and so on. Recently, it has been used to treat different types of malignant carcinoma including intracranial and caudomedial tumors.This study was designed to evaluate the short-term efficacy and toxicity of the CyberKnife radiotherapy for locally advanced pancreatic cancer. Methods: A total of 20 patients with locally advanced (stage Ⅱ-Ⅲ) pancreatic cancer treated with CyberKnife were recruited between April 2009 and December 2009. Of 20 patients, 13 were with cancer located at the pancreatic head and 7 were located at the pancreatic body and tail. The planning target volume (PTV) was defined as gross tumor volume (GTV) plus 2-3 mm, and more than 95% PTV should be covered by 75% isodose surface. The median of PTV was 47 cm3 (26-64 cm3). The median total prescription dose was 40 Gy (32-55 Gy) at 3-6 fractions.During treatment delivery, X-Sight Spine Tracking System was used in 5 patients to track movement of the tumor. Other 15 patients were implanted fiducials in the tumors to track movement of the tumor and patient breathing pattems. Results:The median follow-up time was 7 months (3-11 months). All patients had finished the treatment and 19 were alive by the last follow-up. Slight fatigue was the most common complain. Evaluated by CT scan, 6 were complete response, 9 were partial response, 3 were stable disease, and 1 was progression; 1 was dead. There were 6 patients with grade Ⅰ granulocytopenia, 7 with grade Ⅰ nausea, and 5 with grade Ⅱ vomiting. Conclusions: The CyberKnife radiosurgery for the locally advanced pancreatic cancer shows a high rate of local control and minimal toxicity. Long-term follow-up is necessary to evaluate the survival and late toxicity.