Using reversed-phase high-performance liquid chromatography and electrochemical detection with a rapid one-step purification on Sephadex G-10 column, we have developed a sensitive technique to measure p-hydroxyphenylacetic acid (PHPA), the oxidatively deaminated metabolite of p-tyramine, in cerebrospinal fluid (CSF). The method has been shown to offer simplicity, high sensitivity and low cost for the analysis of PHPA. By using this method PHPA can be measured concurrently with the dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in small amounts of CSF (0.5 ml or less). The concentrations of PHPA ranged 4.2 to 17.0 ng/ml with a mean value of 7.8 ng/ml+/-1.1 SEM in lumbar CSF of non-neurological control patients. PHPA value is consistent with the results of earlier studies using different methods. PHPA concentrations in both schizophrenic (4.7+/-0.6 ng/ml, n=11) and epileptic patients (5.8+/-0.4 ng/ml, n=28) were significantly lower than those in control patients. A concentration gradient of PHPA was found along the ventricular-lumbar axis. Probenecid markedly increased PHPA in lumbar CSF. These observations suggest that PHPA in lumbar CSF is derived at least in part from the brain and eliminated from CSF by a probenecid-sensitive transport mechanism. There was a significant correlation between PHPA and HVA concentrations in CSF. This is an interesting finding since a reciprocal relationship between dopamine turnover and p-tyramine concentrations has been found in the striatum of experimental animals. A number of recent studies suggest that p-tyramine may act as neurotransmitter or neuromodulator in specific neuronal systems. The present method should be useful in clinical investigations to clarify a functional role of p-tyramine in the brain.