SummaryUsing two‐dimensional sodium dodecyl sulphate–polyacrylamide gel electrophoresis, we found that copper/zinc superoxide dismutase (Cu/Zn‐SOD, SOD‐1) was induced in constructed CCR5 stably transfected HEK 293 cells, but not in mock cells, treated with CCL5. CCL5‐induced SOD‐1 expression was also confirmed in HEK 293‐CCR5 cells and CCR5‐positive granulocyte–macrophage colony‐stimulating factor‐induced human macrophages and murine macrophage RAW264.7 cells. CCL5 and CCR5 interaction induced SOD‐1 expression mainly via MEK–ERK activation. In addition, we provided evidence that upregulation of SOD‐1 by CCL5/CCR5 activation occurred in parallel with the increased release of tumour necrosis factor‐α and nitric oxide and production of intracellular reactive oxygen species as well as enhanced nuclear factor‐κB transcriptional activity in CCR5‐positive RAW264.7 cells. Conversely, the MEK1/2 inhibitor PD98059 significantly inhibited SOD‐1 expression with the decrease of these biological responses. More importantly, inhibition of SOD‐1 activity by disulfiram also strongly inhibited the CCL5‐induced biological effects. These data suggest that SOD‐1 mediates CCR5 activation by CCL5 and that pharmacological modulation of SOD‐1 may be beneficial to CCR5‐associated diseases.