BACKGROUND: Guideline-directed medical therapies (GDMTs), such as beta-blockers, antiplatelet drugs, lipid-lowering drugs, and renin-angiotensin system agents, have been associated with reduced risk of mortality after acute myocardial infarction (AMI). However, this survival benefit conferred by GDMTs in nonagenarians and centenarians (≥ 90 years old) is not well-defined. METHODS: We investigated restricted mean survival times of patients ≥ 90 years of age with first-onset AMI treated with GDMTs from 2007 to 2020 in the Singapore Myocardial Infarction Registry. Primary analyses involved stratification by number of GDMTs prescribed at discharge, with derivation of pairwise restricted mean survival ratios free from all-cause mortality at 1, 3, and 5 years. Secondary analyses evaluated individual GDMTs within combinations of 1-3 GDMTs. RESULTS: The analysis included 3264 patients: 0 GDMTs (561 patients, 17.2%), 1-2 GDMTs (1294 patients, 39.6%), 3 GDMTs (904 patients, 27.7%), and 4 GDMTs (505 patients, 15.5%), with a median follow-up duration of 5.71 years. Patients who received 4 GDMTs at discharge were younger, had more comorbidities, were more likely to be smokers, and were more likely to have undergone percutaneous coronary intervention than those prescribed fewer GDMTs. A greater number of GDMT classes at discharge was associated with longer survival free from all-cause mortality at 1, 3, and 5 years. Each drug class within combinations of 1-3 GDMTs was associated with significant survival benefit at all time points, except for beta-blockers. CONCLUSIONS: Prescription of any number of GDMTs to nonagenarians and centenarians after first-onset AMI is associated with significant survival benefit.