Vasodilation induced by methylnicotinate, a fatty acid- and cyclooxygenase-dependent process, is reduced or absent in patients with schizophrenia. This phenomenon has been suggested to be useful as a diagnostic test for the illness. To determine whether reduced flushing is specific to schizophrenia and is caused by a deficiency in membrane fatty acids, the extent of topically applied methylnicotinate-induced vasodilation was measured in 23 subjects with schizophrenia, 20 subjects with bipolar disorder and 34 healthy volunteers along with red cell fatty acid concentrations and measures of clinical severity. Although there was a significant decrease in an estimate of vasodilation (erythema) compared with healthy volunteers in both schizophrenia and bipolar groups, the schizophrenia group responded significantly less than subjects with bipolar disorder. The reduction in the bipolar group was partly due to a delayed vasodilatory reaction, an effect not observed in subjects with schizophrenia. In subjects with schizophrenia, there were no significant correlations between methylnicotinate response and fatty acid concentrations. The authors conclude that the methylnicotinate procedure can differentiate schizophrenia from other serious mental illness. The methylnicotinate insensitivity in schizophrenia, however, is likely to be due to a deficiency in the fatty acid precursors required for the vasodilatory reaction.