The influence of combining antipsychotics and different classes of psychotropic drugs on treatment outcome in schizophrenia remains unclear. As part of a comprehensive quality management program, we prospectively evaluated two schizophrenia polypharmacy performance measures in a cohort of 1,075 consecutively recruited individuals with schizophrenia in seven psychiatric hospitals. Multiple concurrent antipsychotic and overall psychotropic polypharmacy rates were noticeably high. In case-mix-adjustment models controlling for a variety of confounding baseline parameters, patients discharged with more than one antipsychotic had significantly poorer outcomes with respect to both mental state and social functioning. Prescription of more than three psychotropic agents did not adversely affect social functioning when patients taking more than three were compared to patients given fewer medications. Case-mix models suggest that antipsychotic polypharmacy, while used more often for individuals with chronic disease and more thought disturbance, is only partly a reaction to disease severity. The antipsychotic polypharmacy process measure may be used to identify treatment problems in order to find alternatives to polypharmacy. The measure can be easily assessed in a variety of settings and does not depend on the availability of case-mix data. The rising trend toward polypharmacy in schizophrenia care, which is not supported by current guideline recommendations, warrants critical appraisal.