OBJECTIVES: To evaluate health care costs of patients with schizophrenia and specific comorbidities relative to patients without schizophrenia with the same comorbidities. METHODS: Medicaid insurance claims databases from five states (from 2001-2010) were analyzed. Adults with ≥2 claims for schizophrenia, ≥12 months of continuous eligibility prior to the first diagnosis (index date), and ≥1 claim for important comorbidities (substance abuse, obesity, diabetes, metabolic syndrome, hyperlipidemia, hypertension, coronary artery disease, congestive heart failure, HIV, hepatitis C, and COPD) during the 12 months prior to the index date (baseline period) were selected. Patients with schizophrenia were matched 1:1 with non-schizophrenia control patients based on baseline characteristics (propensity scores) and  comorbidities common in schizophrenia (exact matching factors). All-cause and comorbidity-related monthly healthcare costs were calculated and compared between cohorts using nonparametric re-resampling methods. No adjustment was made for multiplicity. RESULTS: A total of 24,652 schizophrenia and 24,652 patients without schizophrenia were matched. The most common comorbidities were hypertension (48.8%), substance abuse (39.1%), and diabetes (28.4%). The patients with schizophrenia incurred greater all-cause monthly healthcare costs (cost difference [95% CI], $978 [933-1,024]) and comorbidity-related costs (cost difference [95% CI], $288 [269-307]). Schizophrenia was also associated with significantly higher comorbidity-related costs in each comorbidity subgroup (among the three most common comorbidities: 99% higher in hypertension, 293% in substance abuse, and 105% in diabetes). CONCLUSIONS: This study show that patients with schizophrenia and comorbidities common in patients with schizophrenia had higher all-cause and comorbidity-related health care costs compared with patients without schizophrenia with the same comorbidities.