OBJECTIVE: Optimizing antiplatelet therapy is crucial in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary interventions (PCIs). This study aimed to assess the prevalence of CYP2C19 loss-of-function (LOF) variants and evaluate the clinical outcome of ticagrelor, clopidogrel, and aspirin in patients with ACS-PCI. METHODS: This study included patients from the southern part of India (predominantly Tamil Nadu) with coronary artery disease and PCI. They were categorized based on their CYP2C19 LOF variants. Patients were further divided into group 1 (continued ticagrelor) and group 2 (switched to clopidogrel) and followed up for 40 months. The primary and secondary outcomes were evaluated. RESULTS: A total of 287 patients were genotyped, 36.2% were normal, 46.3% were intermediate, and 17.5% were poor metabolizers, the predominant allele being CYP2C19*2. After considering only patients who underwent PCI and received ticagrelor, 111 patients were recruited. Ticagrelor was switched to clopidogrel in 45.9% of patients. No statistically significant differences in major adverse cardiovascular events or individual outcomes were observed among different metabolizer groups and patients switched from ticagrelor to clopidogrel. Intermediate metabolizers (IMs) exhibited a trend favoring ticagrelor continuation. Notably, discontinuation of aspirin in IM was linked to increased target vessel reintervention (TVR) in the clopidogrel-only group. CONCLUSION: Our study provides preliminary evidence on favoring ticagrelor continuation and increased TVR upon aspirin withdrawal in IM.