Electrical currents can be used to produce a block of action potential conduction in whole nerves. This block has a rapid onset and reversal. The mechanism of electrical nerve conduction block has not been conclusively determined, and inconsistencies appear in the literature regarding whether the block is produced by membrane hyperpolarization, depolarization, or through some other means. We have used simulations in a nerve membrane model, coupled with in vivo experiments, to identify the mechanism and principles of electrical conduction block. A nerve simulation package (Neuron) was used to model direct current (dc) block in squid, frog, and mammalian neuron models. A frog sciatic nerve/gastrocnemius preparation was used to examine nerve conduction block in vivo. Both simulations and experiments confirm that depolarization block requires less current than hyperpolarization block. Dynamic simulations suggest that block can occur under both the real physical electrode as well as adjacent virtual electrode sites. A hypothesis is presented which formulates the likely types of dc block and the possible block current requirements. The results indicate that electrical currents generally produce a conduction block due to depolarization of the nerve membrane, resulting in an inactivation of the sodium channels.