Aim To find the causes of clopidogrel resistance caused by high blood glucose from the view of platelet energy metabolism by detection of molecular markers. Methods About 122 patients with coronary artery disease (CAD) accompanying hypertension (HPT) were randomly analyzed. The patients were divided into low response group (LRG) and response group (RG) according to the inhibition of their platelet through the way of ADP inhibition rate in thrombelastogram (TEG). 19 cases (hyperglycemia group)were randomly selected from the group of LRG with hyperglycemia, and 20 cases (no hyperglycemia group) were randomly selected from the group of RG without diabetes or with normal glucose tolerance test. Fresh platelets were isolated for ATP and mitochondrial membrane potential (Δψm) analysis. ATP contents were determinated by luciferin/luciferase luminometric method, and the flow cytometry technique was adopted to evaluate Δψm. In all participants correlation between platelet ATP content, Δψm and other variables was analyzed by a multivariable stepwise regression. Results Platelet ATP contents were significantly higher in hyperglycemia group (4.369±2.174 mmol/g) than in no hyperglycemia group (1.628±0.452 mmol/g； P<0.001). Interestingly, Δψm was markedly decreased in patients of hyperglycemia group (0.484±0.118) compared with no hyperglycemia group (2.381±0.194; P<0.001). For whole subjects, a liner stepwise regression showed that plasma glycated hemoglobin A1c (HbA1c) level was positively correlated to platelet ATP content (β=1.235; P=0.000), and negatively correlated to Δψm (β=－0.54; P=0.000). Although, the age of the patients was involved in the regression equation, but significant correlation (β=0.03; P=0.006) was found between Δψm and HbAlc instead of age. Conclusion High blood glucose leads platelet to produce more ATP, resulting in increased platelet activity, making it easier for patients with high blood glucose to develop Clopidogrel resistance (CR). At the same time, high blood glucose reduces the Δψm of platelets, promoted early apoptosis, indirect CR may be induced.