Serum from 3 of 4 patients with classical Guillain-Barre syndrome 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 [experimental allergic neuritis], EAE [experimental allergic encephalomyelitis] and anti-Gal-Cer [galactocerebroside]), are notably slower in evolution. Conduction block does not begin until more than 24 h after injection and is maximal at about 5 days. Between 6-8 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 10-15 days. Six control human sera injected into 13 sciatic nerves showed no comparable effect. Correlative morphological studies indicate that these Guillain-Barre 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-Barre syndrome, which given access to the endoneurial environment produces active demyelination with conduction block. The production of this factor could be responsible for the polyradiculoneuropathy of this disease.