Objectives: Studies concerning metabolic effects associated with second generation antipsychotics (SGAs) have failed to examine the impact of psychiatric comorbidities or medications. This study aimed to determine the association of metabolic syndrome (MetS) and SGAs, and the incremental contributions of select psychiatric comorbidities and polypharmacy to MetS and expenditures of antipsychotic users with MetS. Methods: Descriptive and regression analyses were applied in 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 psychiatric drugs with metabolic effects (selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs], other antidepressants, and mood stabilizers). Outcomes of interest included MetS and total medical expenditures (all-cause, non-psychiatric and psychiatric-related). Results: Of 50,128 antipsychotic users, prevalence of MetS was lower in SGA users than non-SGA users (7.6% vs. 12.8%; p<.0001). Non-SGA users were older and had higher prevalence of MetS components. However, SGA users exhibited more indicators of psychiatric severity, evidenced through higher prevalence of psychiatric disorders and higher psychiatric polypharmacy. Multivariable regression analysis showed lower odds of MetS in SGA users (OR=0.86; p<.001) than non-SGA users. Concomitant use of antidepressants including SSRIs and TCAs significantly increased the odds of MetS (OR=1.26 and 1.29, respectively), as did diagnoses of schizophrenia, bipolar or depression (OR=1.22, 1.18, 1.12, respectively) (all p<.001). Among MetS patients, total medical expenditures were higher in SGA users than non-SGA users (median $15,077 vs. $7,776, respectively; p<.0001). Controlling for select psychiatric comorbidities and polypharmacy in antipsychotic users with MetS, SGA use increased total medical expenditures by 16.6 % (p<.0001). Psychiatric comorbidity and polypharmacy also significantly contributed to total medical expenditures by 23-30% (p<.001). Conclusion: Psychiatric comorbidity and polypharmacy increased the odds of MetS in antipsychotic users and contributed to higher expenditures in antipsychotic users with MetS. Findings suggest besides metabolic effects, clinicians need to consider patients' psychiatric comorbidity and polypharmacy burdens when prescribing SGAs.