OBJECTIVES: Current studies examining metabolic effects associated with second generation antipsychotics (SGAs) do not consider the impact of psychiatric comorbidities or medications. This study aimed to determine the association of metabolic syndrome (MetS) and SGA use, and the incremental contributions of select psychiatric comorbidities and polypharmacy. METHODS: We applied descriptive and regression analyses to a large administrative claims database of antipsychotic users to examine the association between SGAs (aripiprazole, ziprasidone, risperidone, quetiapine, and olanzapine) and MetS, as well as the effects of psychiatric comorbidity and polypharmacy. Select psychiatric comorbidities included schizophrenia, bipolar, depression, and other psychiatric disorders. Psychiatric polypharmacy was defined as concomitant use of antipsychotics with other psychiatric drugs with metabolic effects (selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs], other antidepressants, and mood stabilizers). RESULTS: Of 50,128 antipsychotic users, the prevalence of MetS was lower in SGA users than non-SGA users (7.6% vs. 12.8%; p<0.0001), who were older and had higher prevalence of MetS components. However, SGA users exhibited more indicators of psychiatric severity, as evidenced through higher prevalence of psychiatric disorders and higher concomitant use of other psychiatric drugs. Multivariable regression analysis showed the odds of MetS was lower in SGA users (OR=0.86; p<0.001) than non-SGA users. Concomitant use of SSRIs and TCAs significantly increased the odds of having MetS (OR=1.26 and 1.29, respectively), as did diagnoses of schizophrenia, bipolar or depression disorders (OR=1.22, 1.18, 1.12, respectively) (all p<0.001). CONCLUSIONS: Psychiatric comorbidity and polypharmacy significantly increase the odds of MetS in antipsychotic users. Findings demonstrate the need for practitioners to consider patients' psychiatric comorbidity and polypharmacy burdens when prescribing SGAs. Results suggest that prescribers of SGAs may be aware of metabolic effects and therefore prescribe non-SGAs to their more metabolically-vulnerable patients. Further research into the complexities of treatment patterns and outcomes in this comorbid population is warranted.