Parasite infection can lead to alterations in the permeability of host plasma membranes. Presented here is the first demonstration that this phenomenon occurs in Plasmodium-infected liver cells. Using the whole-cell patch-clamp technique, volume-regulated anion channel (VRAC) activity was characterized in Huh-7 cells (a human hepatoma cell line) before and after infection with Plasmodium berghei. Consistent with the presence of VRACs, hypotonic bath solution induced large ion currents in Huh-7 cells that rectified outwardly, reversed close to the equilibrium potential for Cl- and were inhibited by tamoxifen, clomiphene, mefloquine and 5-nitro-2, 3-(phenylpropylamino)-benzoic acid (NPPB), with IC50 values of 4 ± 1, 4 ± 2, 2 ± 1 and 52 ± 12 μM respectively. In isotonic conditions, initial current recordings measured in uninfected and immature (24 h post invasion) parasite-infected Huh-7 cells were similar (with conductances of 14 ± 3 versus 19 ± 5 pS/pF). However, in mature (48–72 h post invasion) parasite-infected Huh-7 cells there was a sevenfold increase in currents (with a conductance of 98 ± 16 pS/pF). The elevated currents observed in the latter are consistent with VRAC-like activity and the possible reasons for their activation are discussed.