One of the most frequent and serious complications of endoscopic retrograde cholangiopancreatography (ERCP) is acute pancreatitis. The aim of this study was to evaluate the preventive effect of low-dose heparin (unfractionated or low-molecular-weight heparin) on post-ERCP pancreatitis (PEP) and its side-effects by a systematic review and meta-analysis of clinical trials. Searching PubMed and EMBASE, up to August 2011, two independent reviewers systematically identified prospective clinical trials detecting the effect of prophylactic low-dose heparin on the incidence of PEP, severe PEP, and post-ERCP hemorrhage complications. Four clinical trials fulfilled our selection criteria, with three prospective randomized and one nonrandomized. A meta-analysis of these clinical trials was then performed. A total of 1438 patients were included. Meta-analysis of these trials indicated that there was no significant association between the use of heparin and the reduction of PEP [relative risk (RR) 0.67, 95% confidence interval (CI): 0.44-1.03, P=0.07] and severe PEP (RR 0.62, 95% CI: 0.15-2.60, P=0.51). However, low-dose heparin did not increase the incidence of post-ERCP hemorrhage complications (RR 0.84, 95% CI: 0.34-2.03, P=0.69). This meta-analysis did not demonstrate a statistically significant benefit of prophylactic heparin use for the prevention of post-ERCP pancreatitis. More multicenter trials involving a larger number of patients are needed to show a possible prevention effect of PEP from heparin and its related compounds.