Fatty acid compositions were determined in red blood cell (RBC) ghost membranes of schizophrenic patients before and after haloperidol withdrawal, as well as with age-matched normal male control subjects (n = 22). Patients on haloperidol (HD) received treatment in doses between 5 and 20 mg/day for at least 5 weeks (n = 24). Drug-free patients (n = 19) were free of all psychotropic medications for an average of 40 days. A highly significant decrease in the levels (nmol/ml packed RBC) of polyunsaturated fatty acids (PUFAs), particularly 18:2(n - 6) and 20:4(n - 6), was found in both HD-treated and drug-free patients. This decrease remained in those patients who had withdrawn from HD for more than 5 weeks (n = 10). Concomitantly, the percentage of saturated and monoenoic fatty acids to total fatty acids increased significantly in schizophrenic patients. The resultant fatty acid profile consequently lowers the unsaturation index (UI), which represents the average number of double bonds per fatty acid molecule, in RBC ghost membranes of schizophrenic patients. Furthermore, the decreases in UI were significantly correlated to the increases in "structure order" of RBC ghost membranes as measured by the steady-state fluorescence anisotropy (rs) in normal control and drug-free schizophrenic subjects. Therefore, it is likely that decreased levels of PUFAs in schizophrenic patients might result from a defective uptake of 18:2(n - 6) into RBC membrane phospholipids. Since fatty acid composition of membrane phospholipids affects the relative degree of membrane fluidity, the present results lend further support that RBC membrane dynamics are altered in schizophrenia.