Aim To study the correlation between the antioxidantion of plasma high density lipoprotein (HDL) and circulating microRNA (miRNA). Methods Scavenger receptor group B type Ⅰ deficient (SR-BⅠ－/－) mice as dysfunctional HDL model mice were used to explore the changes of specific miRNA spectrum. From September 2020 to May 1,0 patients with coronary artery disease (CAD) were enrolled in the Department of Cardiology, Zhongnan Hospital of Wuhan University, non-CAD patients in the same period as control group, both groups with HDL cholesterol (HDLC) higher than 1.04 mmol/L. Results Compared with wild-type mice, the plasma miR-135a in SR-BⅠ－/－ mice decreased significantly. Plasma paraoxonase 1 (PON-1) activity decreased in CAD patients, PON-1 activity in control group was positively correlated with HDLC level, but not in CAD group. The plasma miR-135a level in CAD patients also decreased, and was positively correlated with PON-1 activity. In CAD group, the level of plasma miR-17 decreased significantly, and the levels of miR-223 and miR-760 increased significantly, but there was no correlation with HDLC level or plasma PON-1 activity. Conclusion The level of plasma miR-135a decreased significantly in CAD patients with high HDLC, and was positively correlated with PON-1 activity, which may be related to the antioxidant function of HDL.