Abstract Background Benefits of elevated high-density lipoprotein cholesterol (HDL-C) levels are challenged by reports demonstrating U-shaped relations between HDL-C levels and all-cause mortality; the association with cause-specific mortality is less studied. Methods A total of 344 556 individuals (20–79 years, 52 % women) recruited from population-based health screening during 1985–2003 were followed until the end of 2018 for all-cause and cause-specific mortality by serum HDL-C level at inclusion of <30, 30–39, 40–49, 50–59, 60–69, 70–79, 80–89, 90–99 and >99 mg/dl (< 0.78, 0.78–1.01, 1.04–1.27, 1.30–1.53, 1.55–1.79, 1.81–2.04, 2.07–2.31, 2.33–2.56, >2.56 mmol/L). Hazard ratios (HRs) were adjusted for sex, age, calendar period, smoking, total cholesterol, triglycerides, systolic blood pressure, physical activity, educational length, body mass index and ill health. Results During a mean follow-up of 22 years, 69 505 individuals died. There were U-shaped associations between HDL-C levels and all-cause, cancer and non-cardiovascular disease/non-cancer mortality (non-CVD/non-cancer), whereas for CVD there was increased risk of death only at lower levels. With HDL-C stratum 50–59 mg/dl (1.30–1.53 mmol/L) as reference, HRs 95% confidence intervals (CIs) for levels >99 mg/dl (>2.56 mmol/L) were 1.32 (1.21–1.43), 1.05 (0.89–1.24), 1.26 (1.09–1.46) and 1.68 (1.48–1.90) for all–cause, CVD, cancer and non–CVD/non–cancer mortality, respectively. For HDL-C levels <30 mg/dl (0.78 mmol/L), the corresponding HRs (95% CIs) were 1.30 (1.24–1.36), 1.55 (1.44–1.67), 1.14 (1.05–1.23) and 1.19 (1.10–1.29). The mortality from alcoholic liver disease, cancers of mouth-oesophagus-liver, chronic liver diseases, chronic obstructive pulmonary disease, accidents and diabetes increased distinctly with increasing HDL-C above the reference level. HDL-C levels lower than the reference level were mainly associated with increased mortality of ischaemic heart disease (IHD), other CVDs, stomach cancer and diabetes. Conclusions Higher HDL-C levels were associated with increased mortality risk of several diseases which also have been associated with heavy drinking, and lower HDL-C levels were associated with increased mortality from IHD, other CVDs, gastric cancer and diabetes.