Abstract The effect of Cd 2+ on chloride secretion was examined in A6 renal epithelia cells by chloride-sensitive fluorescence (SPQ probe) and by the short-circuit-current (I sc) technique. Depleting the cells of Cl − suggests that the Cd 2+-activated I sc (ΔI sc(Cd)) is dependent on the presence of Cl − ions. Among the Cl −-channel inhibitors the fenemates, flufenamic acid (FFA) and niflumic acid (NFA), and 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) significantly lowered ΔI sc(Cd) compared with control level. In SPQ-loaded A6 cells, Cd 2+ evoked an increase in Cl − secretion ([ΔCl −] Cd), which significantly exceeded the basal Cl − transport and was blockable by FFA and NFA. The closely related metals, Zn 2+ or Ni 2+, were also able to activate Cl − secretion. Preexposure of Zn 2+ or Ni 2+ completely prevented [ΔCl −] Cd, suggesting that Zn 2+ and Ni 2+ probably use similar mechanisms. Like Cd 2+, thapsigargin (TG), an inhibitor of intracellular Ca 2+-ATPase and the Ca 2+-ionophore A23187, induced an increase in I sc. Moreover, TG and Cd 2+ were able to neutralize the responses of the counterparts as also observed in I sc measurements, which indicates that Cd 2+ activates Cl − secretion in a Ca 2+-dependent manner. Hence, this study supports the idea that basolateral Cd 2+ (possibly also Zn 2+ and Ni 2+), probably through a Ca 2+-sensing receptor, causes calcium mobilization that activates apical fenemate-sensitive chloride channels leading to chloride secretion in A6 cells.