The sympathetic skin response (SSR) detects changes in the electrical potential in the skin in response to physiological and electrical stimuli and, therefore, may indicate the integrity of sympathetic cholinergic neural pathways to sweat glands. This has been evaluated in 21 patients with three forms of peripheral autonomic failure. Of these, 15 had pure autonomic failure (PAF) without additional neurological features; investigations indicated both sympathetic and parasympathetic failure. Four patients had pure cholinergic dysautonomia (PCD), with clinical and laboratory features indicating only cholinergic failure. Two siblings had dopamine-beta-hydroxylase (DBH) deficiency with only sympathetic adrenergic failure. None was on drugs affecting cholinergic function. Ten normal individuals were aged-matched with PAF patients and studied as controls. The SSR was recorded from the palmar hand and plantar foot surfaces, using previously described techniques, in response to physiological (auditory, cough and inspiratory gasp) and electrical stimuli. Nerve conduction studies excluded an associated motor or sensory neuropathy. The SSR was present in all normal individuals, and in both patients with DBH deficiency who had preserved cholinergic and sudomotor function, It was absent in all 15 PAF and all four PCD patients with impaired cholinergic function. Therefore, we conclude that the SSR reflected sympathetic cholinergic function in these three different groups with peripheral autonomic failure.