The role of Cl^- channels in regulatory volume decrease (RVD) in human salivary gland acinar cells was examined using a whole-cell patch clamp technique. Human tissues were obtained from healthy volunteers or from patients with oromaxillofacial tumors. During the measurements, K⁺-free solutions were employed to eliminate contamination of whole-cell conductance by K⁺ currents. When the cells were exposed to a 70% hypotonic solution, outward-rectifying currents, which were not observed in the resting state, were found to have significantly increased both in human labial and parotid gland acinar cells. The amplitudes of the currents were reduced in a low ^- bath solution. Furthermore, the addition of 100μM 5-Nitro-2- (3-phenyl propylamino) benzoic acid (NPPB) or 100μM 4,4'-diisothio cyanatostilbene-2,2'-disulphonic acid (DIDS), known to partially block Cl^- channels, significantly inhibited these currents. Its outward-rectifying current profile, shift in reversal potential in a low Cl^- bath solution and pharmacological properties suggest that this is a Cα²⁺ independent, volume activated Cl^- current. We conclude therefore that volume activated Cl^- channels play a putative role in RVD in human salivary gland acinar cells.