We and others have obtained data both in vivo and in isolated nerve preparations suggesting that Li+ increases the potency of local anesthetics in the block of conduction. In the present study we have tested the hypothesis that Li+ increases the potency of local anesthetic-induced block of conduction via a shift in the potency of local anesthetic-induced block of voltage-gated Na+ channels. To test this hypothesis we have used whole cell patch-clamp electrophysiological techniques on isolated adult rat sensory neurons. The presence of Li+ significantly increased the potency of lidocaine-induced block of both tetrodotoxin (TTX)-sensitive and TTX-resistant voltage-gated Na+ currents: ED50 values for lidocaine-induced block of both currents in the presence of Li+ were less than 35% of the values obtained in the presence of Na+. Li+ effects were dependent on the state of the Na+ channel. It increased the potency of lidocaine-induced block of resting or closed channels, without a detectable influence on use-dependent block or block of channels in the inactivated state. Li+ alone had no detectable effect on the gating properties of voltage-gated Na+ currents present in sensory neurons. The effects of Li+ were concentration-dependent. These results support the suggestion that the influence of Li+ on lidocaine-induced conduction block reflects an increase in potency of lidocaine-induced block of voltage-gated Na+ channels. This increase in potency appears to reflect an increase in the affinity of the low-affinity binding site for local anesthetics. Including Li+ in lidocaine preparations may be an effective way to increase the safety factor associated with the use of this anesthetic clinically.