Lidocaine is a widely used local anesthetic and antiarrhythmic drug that is believed to exert its clinically important action by blocking voltage-gated Na+ channels. Studies of Na+ channels from different species and tissues and the complexity of the drug-channel interaction create difficulty in understanding whether there are Na+ channel isoform specific differences in the affinity for lidocaine. Clinical usage suggests that lidocaine selectively targets cardiac Na+ channels because it is effective for the treatment of arrhythmias with few side effects on muscle or neuronal channels except at higher concentrations. One possibility for this selectivity is an intrinsically higher drug-binding affinity of the cardiac isoform. Alternatively, lidocaine may appear cardioselective because of preferential interactions with the inactivated state of the Na+ channel, which is occupied much longer in cardiac cells. Recombinant skeletal muscle (hSkM1) and cardiac sodium channels (hH1) were studied under identical conditions, with a whole-cell voltage clamp used to distinguish the mechanisms of lidocaine block. Tonic block at high concentrations of lidocaine (0.1 mM) was greater in hH1 than in hSkM1. This was also true for use-dependent block, for which 25-microM lidocaine produced an inhibition in hH1 equivalent to 0.1 mM in the skeletal muscle isoform. Pulse protocols optimized to explore inactivated-state block revealed that hSkM1 was five to eight times less sensitive to block by lidocaine than was hH1. The results also indicate that relatively more open-state block occurs in hSkM1. Thus, the cardiac sodium channel is intrinsically more sensitive to inhibition by lidocaine.