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Few studies have examined the relationship between antipsychotic polypharmacy and metabolic syndrome in schizophrenia. Some studies suggest that antipsychotic polypharmacy may be associated with greater metabolic risk, whereas other studies suggest that this is uncertain. To date, there have been no studies in Egypt or the Arab world that have investigated this relationship. We sought to compare subjects with schizophrenia receiving antipsychotic polypharmacy and monotherapy as regards metabolic outcomes and to investigate medication-related factors associated with metabolic syndrome.We recruited 118 subjects with schizophrenia and compared between those receiving antipsychotic polypharmacy (86 subjects) and monotherapy (32 subjects) as regards demographic, clinical, metabolic, and antipsychotic medication characteristics. We examined the effect of antipsychotic-related factors an outcome of metabolic syndrome.The prevalence of metabolic syndrome in our sample was 38.1%. Except for gender, there was no statistically significant difference as regards demographic and clinical characteristics, rates of metabolic syndrome, or for individual metabolic parameters. We found a statistically significant difference (P < 0.05) between the 2 groups as regards the number, dose, and duration of intake and for the number of subjects receiving typical antipsychotics (oral and depot) and a number of individual antipsychotic medications. Using logistic regression, receiving haloperidol depot was the only antipsychotic-related factor predictive for metabolic syndrome.The prevalence of metabolic syndrome does not differ in schizophrenia whether patients are receiving polypharmacy and monotherapy nor do they differ for individual metabolic parameters. Most antipsychotic-related characteristics did not predict for metabolic syndrome.