We have investigated hypotheses that link the stiff-man syndrome to an imbalance of neurotransmitter systems. No evidence was found to support the concept of defective synaptic transmission at either cholinergic input to Renshaw inhibitory elements or at glycinergic inhibitory input to motoneurons from spinal interneurons, since neither physostigmine nor glycine altered symptomatology. Urinary excretion of the norepinephrine metabolite 3-methoxy-4-hydroxy-phenyl glycol showed a high correlation with clinical status. This suggests the involvement in the stiff-man syndrome of a central norepinephrine neuronal system that has net excitatory effects upon motoneurons, a system whose activity can be increased slightly by levodopa and decreased markedly by diazepam, with corresponding changes in stiffness.