We iontophoresed acetylcholine on the dorsum of the foot and simultaneously measured flare and sweat responses using laser Doppler and sudorometric techniques, respectively. We compared these responses with those induced by histamine. Both acetylcholine and histamine produced dose-dependent flare, but only acetylcholine produced sweat responses. Responses to acetylcholine and histamine were blocked by hexamethonium chloride and pyrilamine maleate, respectively (p less than 0.01). We compared flare and sweat responses in 26 control subjects, 21 asymptomatic diabetic patients and 41 patients (17 diabetic, 24 nondiabetic) with pain symptoms suggestive of small fiber neuropathy and normal sensation (n = 15) or mild to moderate (n = 19) or severe (n = 7) sensory loss. No patient had trophic foot lesions. Basal skin blood flow and maximal flare responses were not significantly different among the various subgroups (Control subjects, 49 +/- 7.4; asymptomatic diabetic patients, 29 +/- 4; patients with small fiber neuropathy and normal sensation, 34 +/- 6; with neuropathy and mild to moderate sensory loss, 29 +/- 4.8; and with neuropathy and severe sensory loss, 35 +/- 5 ml/100 gm, for flare response, respectively). Flare responses lower than the lowest found in control subjects occurred in 5 of 21 asymptomatic diabetic patients, 4 of 15 patients with small fiber neuropathy and normal sensation, 5 of 19 with neuropathy and mild to moderate sensory loss, and 1 of 7 with neuropathy and severe sensory loss.(ABSTRACT TRUNCATED AT 250 WORDS)