The relationship between the time course of clinical response to clozapine and the time course of clozapine plasma levels has never been investigated. In the present study, we assessed prospectively the clinical response to clozapine and the plasma levels of the drug and its major metabolites in 32 drug-resistant patients with schizophrenia kept on a fixed dose of 600 mg/day for 1 year Four of the patients met response criteria at week 4 of treatment. At weeks 8, 12, and 24, new responders were 7, 6, and 6, respectively. Nine patients never achieved clinical response. In responders at week 4, clozapine and clozapine-N-oxide plasma levels were significantly higher than in both new responders at weeks 8, 12, and 24 and nonresponders. In new responders at weeks 8, 12, and 24, in spite of a fixed clozapine daily dose, mean drug plasma levels progressively rose up to when clinical response occurred; then, the levels remained stable over time. Nonresponders exhibited mean clozapine plasma levels constantly below the value of 260 ng/ml, with N-demethylation as the preferred metabolic route. The present findings show, for the first time, that the time course of the clinical response to clozapine may be linked to the time course of plasma levels of clozapine and its major metabolites.