The importance of antipsychotics in the treatment of schizophrenia has been documented in numerous clinical trials. In addition to its established superiority over other antipsychotics in treatment-resistant patients, clozapine has been consistently shown to improve psychopathology and other psychosocial outcome variables in patients with schizophrenia. To determine whether the course of the illness has an influence on response and side-effects to clozapine, we directly contrasted first- and multiple-episode patients with schizophrenia, who had histories of failing response to traditional antipsychotics, during the acute treatment phase. Thirty-nine first-episode patients with schizophrenia and 56 patients who had suffered from at least two episodes of this illness were investigated. Severity of illness and clinical improvement were rated by means of the CGI Scale. Vital signs were recorded weekly. Side-effects were regularly assessed with the UKU Side Effect Rating Scale. Compliance was regularly assessed by clinical interviews and plasma level monitoring. By using comparable mean clozapine doses, the number of treatment responders was similar in both groups (first-episode patients, 51.3%; multiple-episode patients, 46.4%). However, we found a negative association between age and response rate. With regard to side-effects, we could not find any significant difference between groups. Altogether, response and side-effects to clozapine treatment do not seem to be determined by the chronicity of the disorder.