Abstract Objective The POPular AGE trial showed that clopidogrel significantly reduced bleeding risk compared with ticagrelor without any signs of an increase in thrombotic events. The aim of this analysis was to estimate the long-term cost-effectiveness of clopidogrel compared with ticagrelor in these patients aged 70 years or older with non-ST-elevation acute coronary syndrome (NSTE-ACS). Methods and results A 1-year decision tree based on the POPular AGE trial in combination with a lifelong Markov model was developed to compare clopidogrel with ticagrelor in terms of clinical outcomes, costs, and quality-adjusted life years (QALYs) in elderly patients (above 70 year) with NSTE-ACS. Cost-effectiveness was assessed from a Dutch healthcare system perspective. Events rates and utility data observed in the POPular AGE trial were combined with lifetime projections to evaluate costs and effects for a fictional cohort of 1000 patients. Treatment with clopidogrel instead of ticagrelor led to a cost saving of €1484 575 (€1485 per patient) and a decrease of 10.96 QALYs (0.011 QALY per patient) in the fictional cohort. In an alternative base case with equal distribution over health states in the first year, treatment with clopidogrel led to an increase in QALYs. In all scenario analyses, treatment with clopidogrel was cost-saving. Conclusion Clopidogrel is a cost-saving alternative to ticagrelor in elderly patients after NSTE-ACS, though regarding overall cost-effectiveness clopidogrel was not superior to ticagrelor, as it resulted in a small negative effect on QALYs. However, based on the results of the alternative base case and clinical outcomes of the POPular AGE trial, clopidogrel could be a reasonable alternative to ticagrelor for elderly NSTE-ACS patients with a higher bleeding risk.