The role of high-density lipoprotein cholesterol (HDL-C) in heart failure (HF) outcomes is contentious. We aimed to assess HDL-C's prognostic value in HF patients. In this retrospective cohort study (2012-2022) at the First Affiliated Hospital of Xinjiang Medical University, we analyzed 4442 patients, categorized by HDL-C quartiles. We applied the Cox proportional hazards model to assess survival and report hazard ratios (HR) with 95% confidence intervals (CI). Over a decade, we recorded 1354 fatalities (42.3%) and 820 readmissions. The third HDL-C quartile (0.93-1.14 mmol/L) showed the lowest mortality rates, with reduced risks in the second and third quartiles compared to the first (Q2 HR=0.809, 95% CI 0.590-1.109; Q3 HR=0.794, 95% CI 0.564-1.118). The fourth quartile presented a lower mortality risk compared to the first (Q4 HR=0.887, 95% CI 0.693-1.134). A significant correlation existed between HDL-C levels and cardiovascular risk (HR=0.85, 95% CI 0.75-0.96, p<0.01). HDL-C levels exhibit a complex association with mortality in HF, indicating the importance of HDL-C in HF prognosis and the need for tailored management strategies.