OBJECTIVE: Cardiovascular diseases remain a leading cause of morbidity and mortality worldwide. The angiotensin-converting enzyme (ACE) insertion/deletion (I/D) and ACE rs4343 polymorphism have been considered important and extensively studied for their association with cardiovascular conditions. This study investigates the association of this variant with the development of major adverse cardiovascular events (MACE) in hypertensive patients of Khyber Pakhtunkhwa, Pakistan. METHODS: This prospective cohort study, conducted over two years (2022-2023), included 429 adult patients (aged 30-70 years) with cardiovascular risk factors or established cardiovascular disease. Baseline demographic, clinical, and laboratory data were collected. Blood samples were analysed for ACE I/D and ACE (rs4343) polymorphism using polymerase chain reaction (PCR). Participants were followed up for 12 months to monitor MACE occurrence. The study protocol was approved by the institutional ethics committee. Data were analysed using SPSS software for relevant descriptive and inferential statistics. RESULTS: Mean age of the patients was 60.4 years, with 51.3% being male. ACE ID (heterozygous) variant was the most prevalent (67.6%), followed by the II (Insertion) (28%), and the DD (deletion) (4.4%). Significant associations were observed between the ID genotype and specific cardiovascular parameters, particularly ejection fraction (p = 0.019) and pulmonary arterial hypertension (p = 0.008). Most participants (69.2%) had hypertension for over 10 years, and 78.1% were aware of their condition. Genotypes and allele frequencies were also found to be considerably Non-contrasting between the case and control groups for ACE (rs4343). CONCLUSION: The findings demonstrate significant associations between ACE I/D polymorphism and cardiovascular events in patients with hypertension. The rs4343 variant carries no significant affinity for hyperactive ACE, which causes MACE in the subjects of this study.