Aim To investigate the effect of hyperhomocysteinemia (Hhcy) on serum high density lipoprotein (HDL) and apolipoprotein AⅠ (ApoAⅠ) in healthy people. Methods A total of 1980 normal healthy people was recruited without hypertension, diabetes and other diseases. According to whether the HHcy, the subjects were divided into two groups:HHcy group and control group. Biochemical parameters such as fasting blood glucose, fasting insulin and blood lipid were measured. ApoAⅠ was measured and the homeostasis model assessment index of insulin resistance was calculated. Results The level of serum high density lipoprotein cholesterol (HDLC) and ApoAⅠ in HHcy group was significantly lower than that in control group (1.16±0.25 mmol/L vs 1.27±0.31 mmol/L, 1.37±0.19 g/L vs 1.46±0.26 g/L, all P＜0.01). Correlation analysis showed that after adjusting for age, body mass index and triglyceride levels, blood homocysteine (Hcy) level was significantly negatively correlated with HDLC and ApoAⅠ (r＝－0.10, r＝－0.11, P＜0.05). Multiple regression analysis showed that the blood Hcy level was the independent influencing factor of blood ApoAⅠ (β＝－0.067, P＜0.05). Conclusions HHcy is associated with low HDL. HHcy may lead to atherosclerosis in healthy people by decreasing the levels of HDL and ApoAⅠ. Clinically, HHcy should be actively treated.