To investigate whether activation of afferent and central baroreceptor pathways could differentiate between pure autonomic failure (PAF) and multiple system atrophy with autonomic failure (MSA), we determined the effect of upright tilt on circulating levels of vasopressin in patients with PAF and patients with MSA. We also studied 14 normal subjects, nine of whom developed acute hypotension due to vasovagal syncope. In patients with PAF and in normal subjects with vasovagal syncope, upright tilt induced marked hypotension and a pronounced increase in the plasma concentration of vasopressin (1.1 +/- 0.3 to 38.0 +/- 8.0 pmol/l in PAF and 1.0 +/- 0.2 to 27.4 +/- 7.2 pmol/l in vasovagal syncope, p less than 0.005 for both). In patients with MSA, upright tilt also elicited profound hypotension but circulating levels of vasopressin increased little (0.5 +/- 0.1 to 1.5 +/- 0.3 pmol/l, p less than 0.05). During upright tilt, the plasma concentration of norepinephrine significantly increased in normal subjects but did not increase in patients with autonomic failure. Our results indicate that afferent and central baroreceptor pathways involved in vasopressin release are normal in patients with PAF but are impaired in patients with MSA. Thus, measurement of baroreceptor-mediated vasopressin release appears to provide a clear marker to differentiate between patients with PAF and patients with MSA.