The role of extracellular Ca2+ (Ca2+o) in the modulation of cardiac Cl- currents (ICl) such as those activated by cAMP or swelling is uncertain. The effects of Ca2+o and extracellular cadmium (Cd2+o) on Cl- currents in cultured chick cardiac myocytes were investigated in Na+- and K+-free internal and external solutions using the whole-cell patch-clamp technique. In the absence of Na+ and K+ internally and externally, the whole-cell current was predominantly ICl. In the absence of cAMP, removal of Ca2+o (+ 1 mM EGTA) resulted in an increase in the current that was suppressed by reduction of Clo- with a rightward shift of the zero-current potential towards the Cl- reversal potential. We designated this current as a Ca2+-inhibitable ICl. Addition of 0·5 mM Cd2+o with or without removal of Ca2+o also resulted in a 1·5- to 2·0-fold increase in ICl that was attenuated by 1 mM DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid). Under similar conditions, ICl activated by Cd2+o (in 1 mM Ca2+o solution) was not further increased by subsequent removal of Ca2+o, suggesting that addition of Cd2+o and removal of Ca2+o activated the same ICl. In contrast, exposure to 1 µM forskolin further enhanced ICl in the presence of Cd2+o. With 10 µM cAMP in the pipette solution, Ca2+-inhibitable ICl could be activated in myocytes that do not possess cAMP-activated Cl- channels, indicating that activation of Ca2+-inhibitable ICl does not require cAMP. In the presence of cAMP, in cells that display the cAMP-activated ICl, removal of Ca2+o resulted in a further increase in ICl, comparable to the Ca2+-inhibitable ICl. The Ca2+-inhibitable ICl was minimized when pipette solutions contained 1·5 µM Ca2+. These results suggest that removal of Ca2+o or application of Cd2+o activates a Ca2+-inhibitable ICl that is distinct from the cAMP-activated ICl.