Patients with acute myocardial infarction (AMI) who have concomitant peripheral artery disease (PAD) represent a subgroup at high risk of subsequent ischaemic events. This post hoc analysis of PRAGUE-18, a multicenter, randomised trial comparing prasugrel versus ticagrelor in primary PCI, analysed the effect of symptomatic PAD and intensity of antithrombotic therapy on the prognosis of AMI patients treated with primary percutaneous coronary intervention (PCI). During 12-month follow-up, de-escalation from intensive antiplatelet therapy to clopidogrel was allowed with the permission of the treating physician for economic reasons. Symptomatic PAD was present in 2.9% of the study population (n = 1230). The presence of PAD did not significantly affect short-term outcome. At one year, the risk of death was higher in patients with concomitant PAD, 49 (4.1%) vs. 6(16.7%), HR 4.211 (1.803-9.830); p = 0,001. All-cause mortality significantly increased only in subgroup of patients who de-escalated to clopidogrel [6.37 (2.16-18.84), p = 0.001] as opposed to those who did not [3.02 (0.72-12.61), p = 0.13]. These findings suggest that long-term intensive antithrombotic therapy may be particularly important for post-AMI patients with concomitant symptomatic PAD and warrant further investigation.