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Antipsychotic polypharmacy (APP) in patients with schizophrenia spectrum disorders (SSDs) is usually not recommended, though it is very common in clinical practice. Both APP and SSDs have been linked to worse health outcomes and decreased levels of physical activity, which in turn is an important risk factor for cardiovascular diseases and premature mortality. This real-world, observational study aimed to investigate antipsychotic prescribing patterns and physical activity in residential patients and outpatients with SSDs. A total of 620 patients and 114 healthy controls were recruited in 37 centers across Italy. Each participant underwent a comprehensive sociodemographic and clinical evaluation. Physical activity was monitored for seven consecutive days through accelerometer-based biosensors. High rates of APP were found in all patients, with residential patients receiving more APP than outpatients, probably because of greater psychopathological severity. Physical activity was lower in patients compared to controls. However, patients on APP showed trends of reduced sedentariness and higher levels of light physical activity than those in monopharmacy. Rehabilitation efforts in psychiatric residential treatment facilities were likely to result in improved physical activity performances in residential patients. Our findings may have important public health implications, as they indicate the importance of reducing APP and encouraging physical activity.