Antiplatelet switching in the management of acute coronary syndrome (ACS) seems to be safe, but prospective data are limited. This retrospective study assessed the safety and efficacy of in-hospital clopidogrel-to-prasugrel switching in patients with ACS. We analysed 525 consecutive patients with ACS admitted to our coronary care unit. We assessed the prevalence and the short-term outcomes of in-hospital clopidogrel-to-prasugrel switching. Bleeding and thrombotic events were assessed using propensity score matching analysis. A total of 468 patients received acetylsalicylic acid and a P2Y12 ADP receptor inhibitor. Medication switching occurred in 117 patients (25 %). Compared with the clopidogrel group, the switching group consisted preferentially of younger males with STEMI, exhibited fewer comorbidities, and had lower ischaemic risk. We found no differences between the switching group and the clopidogrel group in the bleeding rate [3.6 vs. 2.3 %, odds ratio (OR):1.59 95 % confidence interval (CI): 0.26-9.7, p NS], and in adverse cardiac or cerebrovascular events (MACCE) (5 vs. 8.4 %, OR: 0.57 95 % CI 0.16-2, p NS). In-hospital switching from clopidogrel to prasugrel in a selected high-risk ACS population resulted in a similar incidence of in-hospital haemorrhagic and thrombotic events. This strategy should be clarified in further randomised studies.