Based on the latest knowledge and technological advancements, it is still debatable whether a modern revascularisation approach in the setting of acute myocardial infarction (AMI), including complete revascularisation (in patients with significant non-culprit lesions) with newer-generation highly biocompatible drug-eluting stents, requires prolonged dual antiplatelet therapy (DAPT). TARGET-FIRST (ClinicalTrials.gov: NCT04753749) is a prospective, open-label, multicentre, randomised controlled study comparing short (one month) DAPT versus standard (12 months) DAPT in a population of patients with non-ST/ST-segment elevation myocardial infarction, completely revascularised at index or staged procedure (within 7 days), using Firehawk, an abluminal in-groove biodegradable polymer rapamycin-eluting stent. The study will be conducted at approximately 50 sites in Europe. After a mandatory 30-40 days of DAPT with aspirin and P2Y12 inhibitors (preferably potent P2Y12 inhibitors), patients are randomised (1:1) to 1) immediate discontinuation of DAPT followed by P2Y12 inhibitor monotherapy (experimental arm), or 2) continued DAPT with the same regimen (control arm), up until 12 months. With a final sample size of 2,246 patients, the study is powered to evaluate the primary endpoint (non-inferiority of short antiplatelet therapy in completely revascularised patients) for net adverse clinical and cerebral events. If the primary endpoint is met, the study is powered to assess the main secondary endpoint (superiority of short DAPT in terms of major or clinically relevant non-major bleeding). TARGET-FIRST is the first randomised clinical trial to investigate the optimisation of antiplatelet therapy in patients with AMI after achieving complete revascularisation with an abluminal in-groove biodegradable polymer rapamycin-eluting stent implantation.