Highly sensitive radioimmunoassays were applied to study the sulfoxidation of fluphenazine in 30 schizophrenic patients maintained on either 5 mg or 25 mg fluphenazine decanoate by intramuscular injection every 14 days over a period of 6 months. The presence of the sulfoxide metabolite was detected in all but one of the patients, such that 97% of the 340 plasma samples analysed contained the metabolite. Interpatient variations in plasma levels of fluphenazine, fluphenazine sulfoxide, and in drug to metabolite plasma level ratios were several fold higher than the corresponding intrapatient variations at both dosages. There were statistically significant tendencies for mean plasma fluphenazine levels to rise and mean plasma sulfoxide levels to fall over the 6-month period of study among patients on the high dose, consistent with our previously reported observation that it takes 3-6 months to establish a steady state of fluphenazine with this dosage regimen. By contrast, there were no statistically significant changes in mean plasma levels of either fluphenazine or its sulfoxide in patients on the low dose. Nevertheless, there was a significant rise in fluphenazine to fluphenazine sulfoxide mean plasma level ratios in both dosage groups. It is difficult to assess the significance of the changes in the drug to metabolite ratios with time, since there are no kinetic data on the phase II metabolism (conjugation) of fluphenazine or fluphenazine sulfoxide. This study shows that sulfoxidation is an important major pathway in the metabolism of intramuscularly-administered fluphenazine, and implies that metabolic sites other than gut wall are also involved in the process.