Abstract : The current study was designed to evaluate the effect of EECP therapy with or without trimetazidine(TMZ) in patients with refractory angina via modulating peripheral monocyte expression of Toll like receptor4 (TLR4) and its downstream signaling. A randomized double blind control trial in which 88 stable refractory angina patients allocated into two groups, Enhanced External Counter Pulsation (EECP) group: include 44 patients with stable refractory angina were treated with EECP-Therapy. TMZ-EECP group: include 44 patients with stable refractory angina which gave TMZ 35 mg twice daily in addition to EECP-Therapy. TLR4 levels were assayed in peripheral monocyte by flow cytometry and 8-iso-prostaglandin F2α (8-iso-PGF2 α), interleukin6 (IL6), high mobility group box-1 protein (HMG- BOX) and monocytes chemoattractant protein-1(MCP-1) were also measured beforethe EECP-therapy and before the TMZ giving to patients, and after 35 hours of EECP treatment ( 7 consecutive weeks ).Inhibition in TLR4 expression in peripheral monocyte in both study groups but significantly lower expression level was observed among the TMZ-EECP group (P<0.05). Inflammatory cytokine (HMG Box-1 protein, MCP-1) were remarkably decreased in both study groups but (HMG Box-1 protein, MCP-1 and IL-6) significantly decreasing level was observed among the TMZ-EECP group (P<0.05). Also, the oxidative stress biomarker 8-iso-PGF2α were remarkably decreased in both study groups but significantly decreasing level was observed among the TMZ-EECP group (P<0.05). Timetizidine and EECP therapy decrease the release of HMGB-1 and also decreases the 8-iso-PGF2α serum level. Thus attenuate the TLR4 expression on peripheral monocytes which affect the downstream signaling of TLR4, resulting in decreasing the TLR4 downstream signaling inflammatory markers such as MCP-1 and IL6 levels which yield improvement in the quality of patient’s life by decrease frequency of angina episodes, decreasing the Short-acting nitrate use and change the exercise tolerance and distance