High levels of substance-P are present in the plasma of patients with carcinoid tumours and some thyrotoxic conditions. The majority of the substance-P in the blood plasma was shown, by immunoassay, to be associated with high molecular-weight material in a complex that could be dissociated by repeated gel-filtration. Smaller amounts of an intermediate molecular-weight (about 65,000 Da) complex were also detected. Chemical crosslinking with glutaraldehyde was used to show that the radioactively-labelled derivative [125I]Tyr-8-substance-P was able to bind to the high-Mr fraction of human plasma and also to human serum albumin. Binding to serum albumin was also demonstrated by equilibrium gel-filtration. Substance-P added to human plasma from a thyrotoxic subject, which contained high endogenous levels of the tachykinin (980 pg/mL), was rapidly degraded during incubation at 37 degrees, whereas the endogenous substance-P was considerably more stable. These results suggest that the binding of substance-P to blood plasma components may play an important role in protecting it against degradation. Furthermore, immunoassay techniques involving prior extraction, which fail to detect the bound substance-P, will give inaccurate measurements of the levels of this peptide in plasma.