Summary: A new sensitive analytical method is described for the quantitation of fluphenazine in 1 ml plasma samples after low oral doses of this antipsychotic agent. The drug is isolated by a simple one step extraction technique and analyzed by high-performance liquid chromatography (HPLC) with coulometric detection. The limit of detection for fluphenazine was 10 pg/ml of plasma and standard curves from 25 to 1,000 pg/ml were linear with an overall coefficient of variation (CV) of <5%. The lowest quantifiable concentration of 25 pg/ml could be determined with a CV of 4.7%. The sensitivity of the HPLC assay was such that plasma concentrations of fluphenazine could be followed for 2 days following administration of a single 10 mg oral dose of fluphenazine dihydrochloride to healthy volunteers. Known metabolites of fluphenazine did not interfere in the assay as they eluted with retention times different from that of fluphenazine.