Serum from 3 of 4 patients with classical Guillain-Barré syndrome has produced conduction block in a large proportion of motor axons following subperineurial injection into 13 rat sciatic nerves. These effects, although qualitatively similar to those previously described for certain experimental sera (EAN, EAE, and anti-Gal-Cer), are notably slower in evolution. Conduction block does not begin until more than 24 hours after injection and is maximal at about 5 days. Between 6 and 8 days the appearance of long latency responses signals return of conduction in previously blocked axons. Thereafter return to control values is rapid and complete within 10 to 15 days. Six control human sera injected into 13 sciatic nerves have shown no comparable effect. Correlative morphological studies indicate that these Guillain-Barré sera produce focal demyelination which evolves pari passu with conduction block. Demyelination appears to evolve both by vesicular disruption and by macrophage mediated myelin stripping. A factor is present in the serum of some patients with Guillain-Barré syndrome, which given access to the endoneurial environment produces active demyelination with conduction block. We believe that the production of this factor could be responsible for the polyradiculoneuropathy of this disease.