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Antipsychotic-associated side effects are well known and represent a significant treatment challenge. Still, few large studies have investigated the overall side effect burden of antipsychotics in real-life settings.To describe the occurrence of side effects and perceived burden of antipsychotics in a large naturalistic sample, taking polypharmacy and patient characteristics into account.Patients (n = 1087) with psychotic disorders were assessed for side effects using the Udvalg for Kliniske Undersøgelser (UKU) side effect rating scale in addition to assessment of clinical and pharmacological data. Statistical analyses were performed controlling for possible confounding factors.Use of antipsychotics showed significant associations to neurologic and sexual symptoms, sedation and weight gain, and > 75% of antipsychotics-users reported side effects. More side effects were observed in patients using several antipsychotics (p = 0.002), with increasing total dose (p = 0.021) and with antipsychotics in combinations with other psychotropic drugs. Patients and investigators evaluated the side effect burden differently, particularly related to severity, gender and antipsychotics dose. Twice as many females described side effect burden as severe (p = 0.004).Patients with psychotic disorders have a high occurrence of symptoms associated with use of antipsychotics, and polypharmacy and female gender are seemingly risk factors for reporting a severe side effect burden. Due to the cross-sectional design evaluation of causality is tentative, and these findings should be further investigated in prospective studies.More side effects were reported with increasing antipsychotic drug quantity and in combination with other psychotropic drugs.Patients and investigators evaluated the side effect burden differently regarding severity, gender and dose of antipsychotics.A gender difference in reporting of several specific side effects was found.