Recent studies proposed reasonable doubts about the good prognosis of very high levels of high-density lipoprotein cholesterol (HDL-c). We aimed to investigate the association between HDL-c levels and all-cause mortality using data from an observational cohort study in northern China from 2006 to 2015. The study population was stratified into six groups by HDL-c levels in mg/dl (<40, 40-49, 50-59, 60-69, 70-79, ≥80). Cox hazards regression models were used to estimate the association between HDL-c levels and all-cause mortality. In total, 100,070 participants (aged 51.9 ± 12.7 years) were included in the current analysis. During a mean follow-up of 8.76 years, 7,362 deaths were identified (mortality rate, 8.40 per 1000 person-years). There was a significant interaction effect between age and HDL-c levels (P for interaction < 0.001). Among individuals aged 65 and older, no significant association was found between HDL-c levels and total mortality. In contrast, HDL-c levels showed a U-shaped relationship with all-cause mortality in younger participants (<65 years old), and very high HDL-c levels (≥80 mg/dl) were independently associated with increased total mortality risk compared with the reference level (60 to 69 mg/dl). These findings suggest that very high HDL-c levels may not represent a good prognosis, especially in younger individuals.