A guided de-escalation of P2Y12 inhibitor treatment is considered as an alternative treatment strategy in ACS patients undergoing PCI. However, the safety and efficacy of this strategy may differ in diabetic vs. non-diabetic patients. The aim of this study was to compare the outcomes of platelet function testing (PFT) guided de-escalation of dual antiplatelet treatment (DAPT) in ACS patients with and without diabetes mellitus.TROPICAL-ACS trial randomized 2610 biomarker-positive ACS patients 1:1 to either standard treatment with prasugrel for 12 months (control group) or to PFT guided DAPT de-escalation. The association and interaction of diabetes on clinical endpoints across treatment groups and on platelet reactivity was investigated. In diabetic patients (n=527, 20.2%), the overall event rates were high and the 1-year incidence of the primary endpoint (cardiovascular death, myocardial infarction, stroke or bleeding ≥ grade 2) did not differ between guided de-escalation and control group patients (12.5% vs. 10.8%; HR 1.17, 95% CI 0.71-1.93, p=0.55). In non-diabetic patients (n=2083, 79.8%), the 1-year incidence of the primary endpoint was lower in the guided de-escalation vs. control group (6.1% vs. 8.5%; HR 0.71, 95% CI 0.52-0.99, p=0.04, pint=0.10) Diabetic patients showed higher platelet reactivity levels in both control (on prasugrel, p=0.01) and guided de-escalation group (on-clopidogrel, p=0.005) patients.Although diabetic status did not significantly interfere with treatment effects of guided DAPT de-escalation, our results suggest that this approach might be safe and effective in non-diabetic patients, whilst further investigation is definitely warranted in diabetic patients.