Recent studies suggests that bleeding complications are associated with worse clinical outcome and survival among patients undergoing coronary angioplasty. Thus, in the last years increasing interests have been focused on strategies to prevent bleeding complications. The administration of protamine after coronary stenting for early sheath removal seems very attractive to minimize local and systemic bleeding complications. Thus, the aim of the current study is to perform a meta-analysis of randomized and non-randomized trials evaluating the benefits and safety of protamine administration after coronary angioplasty. The literature was scanned by formal searches of electronic databases (MEDLINE and CENTRAL) from January 1990 to December 2009. The following key words were used: coronary angioplasty, primary angioplasty, coronary stenting, protamine, heparin neutralization, bleeding complications. Primary endpoints were death and major bleeding complications, respectively. Secondary endpoint was myocardial infarction. A total of 5 trials, 2 randomized and 3 non randomized were included in the meta-analysis, involving 6,762 patients (4,913 or 72.6% in the protamine group and 1,949 or 27.4% in the standard group). Protamine administration was not associated with difference in short-term mortality (2.8% vs. 2.7%, OR [95% CI] = 0.97 [0.69-1.37], P = 0.88, p(het) = 1.0), but with a significant reduction in major bleeding complications (2.4% vs. 4.1%, OR [95% CI] = 0.51 [0.37-0.69], P < 0.0001, p(het) = 0.53, NNT = 58.8). No difference was observed myocardial infarction (0.9% vs. 0.8%, OR [95% CI] = 1.14 [0.63-2.07], P = 0.66, p(het) = 0.89). This meta-analysis shows that protamine administration after percutaneous coronary intervention seems to be safe and associated with a significant reduction in major bleeding complications. Pending the results of larger randomized trials, its use may be considered after coronary angioplasty.