OBJECTIVES: Antipsychotics polypharmacy (AP) has been associated with more adverse drug effects, higher treatment costs, worse clinical outcomes and sudden death. Though, the frequency of such practice may reach 50 % in some clinical settings. The aims of this study were to estimate AP costs and its influence on the direct costs of health care package in a sample of people with mental disorders in São Paulo city, Brazil. METHODS: We used a bottom-up approach for the estimation of direct costs according to public health service provider perspective. Direct costs included  costs with accomodation (residential service), inpatient, outpatient and emergency services and treatment received in the previous month, in 147 subjects with mental disorders living in twenty residential services during the year 2011. We evaluated quality of life, social behavior problems, psychiatric diagnosis, severity of symptoms, sociodemographics characteristics and pattern of health service use. RESULTS: AP was found in 38% of the sample and it was not related with gender, age, severity of psychiatric symptoms, quality of life and social behavior problems. Antipsychotics monotherapy costs were related with the type of antipsychotic: Atypical antipsychotics costs were 167.4 times higher than typical antipsychotic costs. AP mean monthly costs per person varied with the type of association between antipsychotics: typical-atypical associations costs  were U$257.5± U$228.5, while mean costs between two typical antipsychotics were U$4.36 ± U$4.02.  Polypharmacy added U$300.00 dolars per person per month to direct costs of health care (excluding accomodation). For each additional antipsychotic associated, it was observed an additional montlhy costs per person of U$87.5 in the total costs of health care package (health services, treatment and accomodation).  CONCLUSIONS: AP added substantial costs and risks to treatment and to health care costs and quality. This should be taken in account in resource allocation in public policies, especially in low-resources settings.