Whether metabolically healthy obesity (MHO) is associated with longitudinal changes in high-density lipoprotein cholesterol (HDL-C) remains unclear. MHO was defined as participants with overweight and obesity (BMI ≥ 24.0kg/m2, n = 2921), free of history of metabolic diseases, and without abnormalities of blood pressure, fasting blood glucose, hemoglobin A1c, lipid profile, carotid artery and liver ultrasonographic findings at baseline. Metabolically healthy normal weight (MHN) was defined as participants with normal weight (BMI < 24.0kg/m2, n = 9578) and without above-mentioned abnormalities. HDL-C, fasting blood glucose, hemoglobin A1c, and blood pressure were assessed annually. Glucose abnormality was considered if either FBG ≥ 5.6mmol/L or HbA1c ≥ 5.7%; while, high blood pressure (HBP) was considered if either systolic blood pressure ≥ 130mmHg or diastolic blood pressure ≥ 80mmHg during 5years of follow-up. Compared with the MHN group, the adjusted mean difference in HDL-C change rate was - 0.005mmol/L per year [95% confidence interval (CI) - 0.007, - 0.003] for MHO after adjustment for a series of potential confounders. Furthermore, transiting to abnormality of blood glucose, but not high blood pressure, was associated with lower cumulative average of HDL-C in MHN group, compared with those remained in metabolically healthy status. MHO and transiting from metabolically healthy to abnormality of blood glucose were associated with HDL-C in Chinese adults. III, cohort study.