In whole-cell recordings on primary cultures of human hepatocytes, we observe the hypertonic activation of a novel type of cation channel with a permeability ratio for Na(+):Li(+):K(+):Cs(+):NMDG(+) of 1:1.2:1.3:1.2:0.6. With a P(Ca)/P(Na) of 0.7 the channel is also clearly permeable to Ca(++). Most likely, the channel is Cl(-) impermeable but its activity critically depends on the extracellular Cl(-) concentration (with the half maximal effect at 88 mmol/l). With a 64% inhibition by amiloride and a complete block by flufenamate and Gd(3+) (at 100 micromol/l each), the channel may represent a molecular link between the amiloride-sensitive and insensitive channels reported so far.