Extracellular acidic pH activated chloride channels (I(Cl,acid)) have been characterized in HEK 293 cells and mammalian cardiac myocytes. This study was designed to evaluate the expression of I(Cl,acid) in RAW264.7 monocytic-macrophage and human peripheral monocytes and to investigate the effect of simvastatin on I(Cl,acid). In two kinds of cells, the activation and deactivation of the current rapidly and repeatedly followed the change of the extracellular solution to pH=4.3. Compared with the outward current (pA/pF) activated at pH 4.3, the currents inhibited by simvastatin at concentrations of 0.1 microM were all decreased a little, however the currents at concentrations of 1 microM and 10 microM simvastatin were decreased significantly. The IC(50) for simvastatin inhibiting I(Cl,acid) of RAW264.7 was 13.77 microM. In summary, we report for the first time that simvastatin inhibits the I(Cl,acid) of RAW264.7 monocytic-macrophage and human peripheral monocytes in a concentration-dependent manner.