The purpose of this study was to calculate the proportion of patients with schizophrenia receiving persistent antipsychotic polypharmacy and excessive dosing in four European countries; to test the hypothesis that excessive dosing and/or antipsychotic polypharmacy is associated with higher levels of psychopathology; and to establish whether use of second-generation antipsychotics is a protective or a risk factor for polypharmacy and excessive dosing. Participants with schizophrenia were recruited from patients under the care of psychiatric services serving geographical catchment areas in Croydon (UK), Verona (Italy), Amsterdam (Netherlands), and Leipzig (Germany). We defined patients persistently receiving high antipsychotic dose (i.e. excessive dosing) as those with a prescribed daily dose/defined daily dose ratio of >1.5 both at initial assessment and after 1 year of follow-up. Similarly, we defined patients persistently receiving polypharmacy as those being prescribed two or more antipsychotic drugs both at baseline and at follow-up. A sample of 375 participants with schizophrenia was analyzed. A proportion of 28% of patients persistently received high-dose antipsychotic drugs, and a proportion of 13% of patients persistently received antipsychotic polypharmacy. In the multivariate analysis, psychopathology was not a predictor of persistent polypharmacy and excessive dosing; similarly, use of second-generation antipsychotics was not associated with polypharmacy and excessive dosing; however, persistence with high antipsychotic doses was predicted by baseline use of first-generation antipsychotics and second-generation antipsychotics concurrently. Antipsychotic drug use for patients with schizophrenia is only sometimes satisfactory and offers the opportunity of improvement. Clinicians should consider that dose reduction strategies have been shown to be a feasible intervention in patients with schizophrenia.