With the availability of novel P2Y(12) receptor inhibitors, patients presenting with acute coronary syndrome (ACS) may receive more than one type of this drug during index hospitalization. We sought to determine the effect of switching from clopidogrel to a novel P2Y(12) receptor inhibitor on the occurrence of major adverse cardiovascular events (MACE) and bleeding. We conducted a literature search on SCOPUS for English language entries until 7 March 2015. Out of 188 citations, seven studies encompassing 16,431 patients were selected for analysis of (i) switching to a novel P2Y(12) agent (switching group) versus continued clopidogrel or (ii) switching to a novel P2Y(12) agent (switching group) versus upfront novel agent initiation during index hospitalization MACE was significantly lower in the switching group (odds ratio (OR) 0.77, 95 % confidence interval (CI) 0.63-0.96, p = 0.02), whereas bleeding was higher (OR 1.55, 1.29-1.85, p < 0.01) compared with continued clopidogrel. Conversely, MACE was similar with switching to a novel agent and upfront novel therapy initiation (OR 1.01, 95 % CI 0.8-1.29, p = 0.90), but bleeding was higher in the switching group (OR 1.24, 95 % CI 1.03-1.48, p = 0.02). The current study suggests that switching to a novel P2Y(12) agent in patients with ACS and/or patients undergoing coronary stenting is more efficacious than continuing clopidogrel. In this cohort, switching to a novel agent did not result in worse ischemic outcomes than upfront initiation of novel therapies. However, switching was associated with greater bleeding compared with both continued clopidogrel as well as upfront use of novel P2Y(12) agents.