To date numerous in-vivo (31)P-MRS and in-vitro studies in schizophrenic patients have been able to demonstrate changes in their membrane phospholipid metabolism, which might be relevant for the cause and the therapeutic responsiveness of this disorder. Thus far, however, only limited studies exist regarding the specificity of these findings for schizophrenia and the effect of antipsychotic medication. The present study examined the composition of membrane phospholipids in platelets of 67 neuroleptic-free schizophrenic patients compared to healthy and psychiatric controls. In a subsample of the schizophrenic patients we determined the effect of antipsychotic treatment on the phospholipid metabolism during six-months follow up. While untreated patients showed a decrease in major membrane phospholipid components, i.e. phosphatidylcholine and phosphatidylethanolamine, when compared to control subjects, as well as an increase in their breakdown-product lysophosphatidylcholine (LPC), there was a significant reduction in LPC during three weeks of pharmacotherapy with haloperidol. After six months treatment with different antipsychotics some divergent effects on phospholipid metabolism in schizophrenic patients could be demonstrated. While in the long-term course LPC remained decreased under continuous therapy with typical neuroleptics, patients being treated with the atypical drug zotepine showed an increase in LPC compared to their baseline level before therapy. Thus, specific mechanisms of the different antipsychotic therapies on phospholipid metabolism might serve to explain the divergent findings of (31)P-MRS in medicated patients.