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Objectives The purpose of this study was to verify whether guideline-directed medical therapy (GDMT, ie, the combined use of β-blocker, ACE inhibitor/angiotensin receptor blocker, dual antiplatelet drugs and statin) could improve in-hospital mortality in acute coronary syndrome (ACS) patients with advanced renal dysfunction (estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m 2).Design Retrospective cohort study.Setting This study used data from two large, multicentre, observational cohorts: the Chinese National Electronic Disease Surveillance System Platform (CNEDSSP) and the Improving Care for Cardiovascular Disease in China-ACS (CCC-ACS) project. These cohorts consist of ACS patients admitted to 47 and 241 hospitals, respectively, across China from 2014 to 2019.Participants A total of 6260 patients diagnosed with advanced renal dysfunction (eGFR <30 mL/min/1.73 m²) on admission were included in the analysis. Among these, 3013 patients were from the CNEDSSP cohort and 3247 from the CCC-ACS cohort. Patients were categorised based on receipt of GDMT within 24 hours of admission.Main exposure measure The main exposure measure was the early use of GDMT, defined as the administration of all four components of GDMT within 24 hours of hospital admission.Main outcome measure The primary outcome was in-hospital mortality, assessed within the study cohort.Results In a pooled analysis of the CNEDSSP and CCC-ACS cohorts, early GDMT was associated with a significant reduction in in-hospital mortality (relative risk (RR): 0.62, 95% CI: 0.47 to 0.81). More pronounced reductions were observed in myocardial infarction (MI) patients, with HRs of 0.31 (95% CI: 0.17 to 0.55) in the CNEDSSP cohort and 0.47 (95% CI: 0.28 to 0.77) in the CCC-ACS cohort. A random-effects pooled analysis of MI patients with advanced renal dysfunction at admission showed a 61% reduction in in-hospital mortality among GDMT users (RR: 0.39, 95% CI: 0.27 to 0.58).Conclusions This nationwide study highlights that early GDMT is associated with a reduced risk of in-hospital mortality in ACS patients (particularly in MI patients) with advanced renal dysfunction.