Objectives: This study investigates the clinical characteristics and angiographic differences between male and female patients diagnosed with Heart Failure with Reduced Ejection Fraction (HFrEF) at Civil Hospital Karachi, with a focus on gender-related disparities in risk factors and treatment outcomes. Methodology: Conducted from October 2023 to March 2024, this observational study included 150 hospitalized patients (61 females and 89 males) aged 20 to 70 years, who presented with HFrEF and had no prior history of coronary artery disease. Data were collected on demographic information, comorbidities, risk factors, and angiographic findings. Statistical analyses were performed to assess gender differences in clinical presentations and treatment strategies. Results: Of the 150 patients, 61 (40.7%) were female, and 89 (59.3%) were male, with a median age of 56.0 years (range: 22 to 78 years, SD = 11.36). A total of 81 patients had diabetes, of which 62 had uncontrolled diabetes; 139 patients were hypertensive, with 86 experiencing uncontrolled hypertension. The study revealed significant gender differences in angiographic findings (p < 0.001), severity of coronary artery disease (CAD) (p < 0.001), and treatment modalities following left heart catheterization (p = 0.003). Males exhibited a higher prevalence of multi-vessel disease and obstructive CAD compared to females. Conclusion: The findings of this study highlight notable gender-specific differences in the clinical presentation and angiographic outcomes of patients with HFrEF. These results emphasize the importance of considering gender when evaluating risk factors and tailoring treatment strategies in heart failure management, ultimately aiming for improved patient care and outcomes.