: Heart failure with reduced ejection fraction (HFrEF) is associated with significant renal complications, affecting disease progression and patient outcomes. Sodium-glucose co-transporter-2 (SGLT2) inhibitors have emerged as a key therapeutic strategy, offering cardiovascular and renal benefits in these patients. However, interindividual variability in response to dapagliflozin underscores the role of pharmacogenetics in optimizing treatment efficacy. This study investigates the influence of genetic polymorphisms on renal outcomes in HFrEF patients treated with dapagliflozin, focusing on variations in genes such as , , , and . : This prospective, observational cohort study was conducted at the National Heart Institute, Cairo, Egypt, enrolling 200 patients with HFrEF. Genotyping of selected single nucleotide polymorphisms (SNPs) was performed using TaqMan™ assays. Renal function, including estimated glomerular filtration rate (eGFR), Kidney Injury Molecule-1 (KIM-1), and Neutrophil Gelatinase-Associated Lipocalin (NGAL) levels, was assessed at baseline and after six months of dapagliflozin therapy. : Significant associations were found between genetic variants and renal outcomes. Patients with AA genotype of rs3813008 () exhibited the greatest improvement in eGFR (+7.2 mL ± 6.5, = 0.004) and reductions in KIM-1 (-0.13 pg/mL ± 0.49, < 0.0001) and NGAL (-6.1 pg/mL ± 15.4, < 0.0001). Similarly, rs12917707 () TT genotypes showed improved renal function. However, rs5219 () showed no significant impact on renal outcomes. : Pharmacogenetic variations influenced renal response to dapagliflozin in HFrEF patients, particularly in and genes. These findings highlighted the potential of personalized medicine in optimizing therapy for HFrEF patients with renal complications.