Background: Superiority of potent P2Y12 inhibitors over clopidogrel after an acute coronary syndrome (ACS) has been well established, however potent P2Y12 inhibition is responsible for more adverse events, which may influence patient adherence to treatment. Aim of the present study is to investigate the adherence to the prescribed P2Y12 inhibitor (P2Y12i) in patients on dual antiplatelet therapy (DAPT) after an ACS. Methods: In an IDEAL-LDL trial substudy, we included 344 patients after ACS discharged on DAPT. The primary outcome was the difference between potent P2Y12i and clopidogrel in terms of adherence, as well as other predictors of adherence to the antiplatelet regimen. Secondary outcomes included the prevalence of DAPT continuation and its predictors and the antiplatelet regimen selection after DAPT. Results: Adherence to the potent P2Y12i and to clopidogrel was observed in 140/178 (78.7%) and 111/166 (66.9%) patients (p = 0.016), respectively. In the multivariate model, after adjustment for P2Y12i switching during the first year of therapy, there was no difference observed in adherence between potent P2Y12i and clopidogrel (odds ratio [OR] = 0.98, 95% confidence interval [CI] = 0.55–1.74). Significant predictors included history of cardiovascular disease (CVD) (OR = 0.51, 95% CI = 0.31–0.86) and percutaneous coronary intervention (PCI) index event treatment (OR = 2.58, 95% CI = 1.38–4.82). Of patients, 72% continued DAPT >12 months and female gender was a negative predictor of DAPT prolongation (adjusted OR = 0.43, 95% CI = 0.21–0.90). DAPT was continued until the end of follow-up in 42.7%, while 54.6% resumed with single antiplatelet regimen. Conclusions: Adherence to DAPT was not affected by the P2Y12i potency, whereas history of CVD and PCI treatment were associated with reduced and increased adherence, respectively. Clinical Trial Registration: NCT02927808, https://clinicaltrials.gov/ct2/show/NCT02927808.