OBJECTIVES: Studies concerning metabolic effects associated with second generation antipsychotics (SGAs) fail to control for psychiatric comorbidities or medications known to affect weight. We analyzed a large administrative claims database to determine the associations of psychiatric comorbidity and polypharmacy and hospitalization and expenditures among SGA users with metabolic syndrome (MetS). METHODS: Using descriptive and logistic regression analyses, we examined the effects of psychiatric comorbidity and polypharmacy on the association between SGAs (aripiprazole, ziprasidone, risperidone, quetiapine, and olanzapine) and hospitalization and expenditures among antipsychotic users with MetS. Psychiatric comorbidities included schizophrenia, bipolar, depression, and other psychiatric disorders. Psychiatric polypharmacy was concomitant use of antipsychotics with psychiatric drugs with metabolic effects (selective serotonin reuptake inhibitors [SSRI], tricyclic antidepressants [TCA], other antidepressants, and mood stabilizers). We also controlled for sociodemographics and insurance. Outcomes of interest included all-cause hospitalization and expenditures, disaggregated to non-psychiatric and psychiatric-related events. RESULTS: SGA users with MetS were more likely to have hospitalization than non-SGA users with MetS (OR=1.29; P<0.05); however, the association became non-significant upon controlling for psychiatric comorbidity and polypharmacy. Instead, having schizophrenia, bipolar, depression, or other psychiatric disorders significantly increased the odds of hospitalization (ORs=2.56, 1.44, 1.73, 2.06, respectively; all p<0.0001), as did concomitant use of SSRIs or TCAs (ORs=1.35 and 1.36, respectively; both p<0.01). Among MetS patients, total medical expenditure was higher in SGA users than non-SGA users (median $15,077 vs. $7,776, respectively; p<0.0001). Controlling for psychiatric comorbidities and polypharmacy in antipsychotic users with MetS, SGA use increased total expenditures by 16.6 % (p<0.0001). Psychiatric comorbidity and polypharmacy also significantly contributed to total expenditures by 13-30% (p<0.001). CONCLUSIONS: Among patients with MetS, psychiatric comorbidity and polypharmacy are associated with higher risk of hospitalization and expenditures in SGA users than non-SGA users. Findings suggest clinicians should consider patients' psychiatric comorbidity and polypharmacy burdens when prescribing SGAs.