OBJECTIVE: To compare the cost of antipsychotic polypharmacy during the treatment of schizophrenia patients with risperidone, olanzapine, or quetiapine. METHODS: Data were drawn from a large prospective naturalistic study of treatment for schizophrenia in the United States, conducted between 7/1997 and 9/2003. Participants who initiated on risperidone (N=276), olanzapine (N=405), or quetiapine (N=115) were followed for 1-year post initiation and compared on annual cost of all antipsychotic medications, and on daily cost of concomitant antipsychotic medication. Statistical analysis used propensity score adjusted bootstrap re-sampling methods. RESULTS: Quetiapine-treated patients accrued significantly higher annual cost of all antipsychotic medications compared to olanzapine or risperidone (p<.01). The daily cost of concomitant antipsychotic medications was significantly higher for quetiapine ($8.70) compared to olanzapine ($3.82, p<.01) or risperidone-treated patients ($4.30, p<.01). The total daily cost of antipsychotics, including index antipsychotic cost, was $15.33, $13.90, and $11.04 for quetiapine, olanzapine and risperidone, respectively. Each dollar spent on quetiapine-treated patient was accompanied by additional $1.31 on concomitant antipsychotic medication, compared with $0.64 for risperidone, and $0.38 for olanzapine-treated patients. CONCLUSIONS: Prevalent antipsychotic polypharmacy adds substantial cost to the treatment of schizophrenia. A clearer understanding of the concomitant antipsychotic costs provides a more accurate portrayal of medication cost.