The clearance of neurohypophysial peptides from cerebrospinal fluid (CSF) in conscious unrestrained guinea pigs. 125I-labelled peptides were detectable in the cisterna magna within 2 min of their intracerebroventricular injection, reaching peak concentrations 10-15 min post-injection and declining exponentially over the next hour. 125I-oxytocin (125I-OT) and 125I-vasopressin (125(I-AVP) were cleared at similar rates, whereas 125I-labelled neurophysin (125I-NP) disappeared significantly more slowly; mean half-times of clearance (t1/2) from cisternal CSF were 28, 24 and 46 min, respectively. 125I-NP was cleared at the same rate as 3H-inulin (t1/2 40 min), as was an antibody to OT (anti-OT, t1/2 37 min). Intracerebroventricular infusions of iodinated peptides produced constant levels in CSF within 3 h. 125I-AVP reached lower plateau levels and disappeared twice as fast as 125I-NP, although the apparent equilibrium distribution space was the same for both peptides. Although NP was cleared half as fast as OT or AVP, this difference was not sufficient to account for the large molar excess of NP over the nonapeptides in guinea pig CSF. There is an effective blood/CSF barrier to neurohypophysial peptides in the guinea pig; intravenous infusions of OT or porcine NP did not raise the CSF levels of these peptides (measured by specific radioimmunoassays) except when very high concentrations were maintained in peripheral plasma. However, single intravenous injections of anti-OT produced low but significant titres in CSF, persisting for several days.