High-density lipoprotein cholesterol (HDL-C) has long been considered cardioprotective, yet recent studies suggest a U-shaped association with mortality, indicating possible harm at extremely high levels. Evidence from the XXX population remains limited, particularly regarding sex-specific patterns and cause-specific mortality.The study aimed to (1) examine the association between extremely high HDL-C and all-cause and cause-specific mortality, (2) identify sex-specific nadir points in the HDL-C–mortality curve, and (3) evaluate whether the association between HDL-C and mortality is modified by LDL-C levels, and whether extremely high HDL-C remains protective across  LDL-C categories.A nationwide longitudinal cohort from XXX was analyzed, in which participants who underwent baseline health examinations were followed for up to 12.3 years. HDL-C was assessed using categorical groups (10 mg/dL increments) and as a continuous measure using restricted cubic spline models. Outcomes included all-cause mortality and cause-specific mortality (cardiovascular disease [CVD], cancer). Analyses were stratified by sex and adjusted for demographic variables, lifestyle factors, comorbidities, and lipid profiles.During follow-up, 3.8% of participants died. HDL-C exhibited a U-shaped association with all-cause mortality, with nadirs at 40–50 mg/dL in men and 60–70 mg/dL in women. Low HDL-C (<40 mg/dL) was associated with substantially higher CVD mortality across LDL-C categories, with risk rising steeply at the lower range. Associations at extremely high HDL-C levels were less robust. For cancer mortality, low HDL-C showed a modest increase in risk, whereas findings at very high HDL-C levels were weak and not statistically consistent. Extremely high HDL-C did not demonstrate a protective association in any LDL-C category and showed only modest risk elevation at very high levels.The findings support a non-linear, sex-specific relationship between HDL-C and all-cause mortality. The pattern observed across LDL-C categories suggests that extremely high HDL-C may not provide additional protective effects.HDL-C demonstrated a sex-specific U-shaped association with mortality, with men exhibiting a lower nadir than women. Extremely high HDL-C levels may serve as a potential risk indicator rather than a protective marker. These findings highlight the need for careful clinical assessment of HDL-C in the context of overall lipid profiles.