OBJECTIVES: To estimate the national prevalence, socio-demographic and health characteristics, and direct incremental expenditures of of drug-drug interactions (DDIs) involving antipsychotics among adult in united states. METHODS: A retrospective database analysis was conducted and individuals who were exposed to any DDI were identified from the 2010-2014 Medical Expenditure Panel Survey. The prevalence of DDI was evaluated by four international drug interaction compendia. The predictors and expenditures were estimated by employing multiple regression models and the propensity score method. RESULTS: From 2010 to 2014, the national prevalence of DDIs was 4.7 million (36%) with incremental costs of $4,563 per person annually. Adults exposed to DDIs cost 55% more annual total health care expenditures than those are not exposed (RR = 1.55, 95% CI [1.25, 1.92]). Likewise, cost of office-based (RR = 1.78, 95% CI [1.34, 2.38]), and prescription drugs (RR = 2.08, 95% CI [1.55, 2.78]) were significantly associated with exposure to DDIs. Factors associated with greater odds of DDIs exposure were age, sex, race, type of health insurance, general health, and polypharmacy. CONCLUSIONS: The prevalence of DDIs is substantially high among adults using antipsychotics. A significant relationship between the exposure to the DDI and higher total health care expenditures were found. This finding can help policy makers in implement intervention strategies that are effective in lowering the DDI incidence and in reducing the overall cost of care.