Background & Aims: Cystic lesions of the pancreas are detected more often nowadays. Many are considered premalignant and pancreatic resection is recommended. This study was undertaken to assess the natural course of asymptomatic pancreatic cysts and their malignant potential. Methods: All patients referred for endoscopic ultrasound (EUS) between 1994 and 2003 because of pancreatic cystic lesions were included. Results: A total of 135 patients underwent EUS because of pancreatic cysts. Twenty-three patients were excluded because they were symptomatic or had pancreatic pseudocysts. The other 112 patients were diagnosed as having true pancreatic cysts. Fourteen of the 112 patients were referred for surgery based on either unfavorable EUS morphology or fine-needle aspiration results. In 4 (29%) of 14 surgical specimens, the histology was that of malignancy. An additional 8 patients with serous cystadenoma and pseudocysts were excluded from the analysis. The remaining 90 patients were defined as having indeterminate or mucinous cysts and were managed conservatively. The follow-up period lasted between 12 and 180 months (mean, 48 ± 33 mo). Malignancy was diagnosed in only 1 patient after 7 years of follow-up evaluation. None of the 57 patients available for clinical follow-up evaluation became symptomatic. The size of the cyst remained unchanged in 45 patients, increased in 2, and resolved in 9. Thirty-three patients were followed up through the Israel Registry: 31 were alive and 2 died from unrelated causes. Conclusions: Our data suggest that a considerable number of asymptomatic pancreatic cystic lesions can be managed conservatively, at least for a mean period of 4 years. Malignant transformation in pancreatic cystic lesions probably is less frequent than previously reported.