Abstract Background The implementation of guideline-directed medical therapy (GDMT) after acute coronary syndrome (ACS) was reported to improve prognosis. However, there have been limited number of real-world studies clarifying the association between the status of GDMT implementation and clinical prognosis in ACS patients based on recent multicenter database. Purpose The purpose of this study was to survey the extent to which GDMT was performed over time in patients after percutaneous coronary intervention (PCI) for ACS, as well as to investigate the prognostic impact of GDMT. Methods This study is a retrospective, multicenter, observational study. We developed the Clinical Deep Data Accumulation System (CLIDAS), which consists of 6 university hospitals and the national cardiovascular center in Japan, directly obtains clinical data including patients background, laboratory data, echocardiogram, electrocardiogram, cardiac catheterization report, prescription, and long-term outcome from electronic medical records. 4107 patients who underwent PCI for ACS and were prescribed one or more antiplatelet drugs at baseline from April 2013 to March 2019 were analyzed, and divided into GDMT group (n = 2514) and non-GDMT group (n = 1593). GDMT was defined as all prescriptions for angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, beta-blocker, and statin at baseline. The primary outcome was the major adverse cerebrocardiovascular event (MACCE) defined as being the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Results The median follow-up duration was 2.36 years (interquartile range: 0.78-4.00 years). The study cohort consisted of 76% of men with a median age of 71 years. The incidence of MACCE was significantly lower in the GDMT group than in the non-GDMT group (8.8% vs. 13.0%, log rank P <0.001). Multivariable Cox regression analyses revealed that the GDMT group was a lower hazard ratio (HR) for MACCE after adjusting for confounding factors including the information about the first half and the second half (HR, 0.80; 95% confidence interval, 0.65-0.98; P = 0.035). The implementation rate of GDMT in the first half group (from April 2013 to March 2016) was lower than that in the second half group (from April 2016 to March 2019) (58.3% vs. 64.4%, P <0.001). Conclusion The real-world CLIDAS database revealed that GDMT was significantly associated with the reduction of MACCE in patients with ACS after PCI. In addition, an increase in the rate of GDMT implementation over time was observed.Kaplan-Meier curves for MACCE