OBJECTIVES: There is a lack of information about the impact of combination of chronic conditions among US adults on healthcare expenditures. The objective was to estimate the total healthcare expenditures, prescription drug cost and out-of-pocket spending among US adults with at least 2 of the following conditions: Hypertension, Dyslipidemia, Diabetes and Chronic Obstructive Pulmonary Disease (COPD).   METHODS: The Medical Expenditure Panel Survey (MEPS) data of 2013 was used. International Classification of Diseases (ICD9-CM) codes were used to identify above conditions and make 11 mutually exclusive combinations of them. Adults aged 21 years or older, who had at least 2 of the above conditions, were included in the analysis. Data were analyzed using STATA14 for descriptive statistics and differences using the Student t-test and Chi-square test. Regression analysis was performed to predict associations between demographics; combinations of disease conditions, healthcare expenditures and out of pocket spending. Expenditures were adjusted to 2014 US dollars using Consumer Price Index (CPI).  RESULTS: The final sample consisted of 17,103 adults with a mean age was 61.9 yrs. Majority of adults were non-Hispanic white (71%) and were female (52%). Adults with all four conditions had average total healthcare expenditure ($10,935), prescription drug cost ($3,194) and out of pocket cost ($1,281). Among 11 mutually exclusive disease combinations, adults with hypertension/dyslipidemia had the lowest annual healthcare expenditure ($10,033), prescription drug cost ($2,816) and out of pocket spending ($1,238). Gender and age were good predictor of high healthcare expenditures, prescription drug and out of pocket costs (p<0.05). CONCLUSIONS: The total health care expenditures differed by type of chronic disease condition combinations among US adults. New approach for managing patients with multiple chronic conditions is needed to reduce the total healthcare cost, out of pocket and prescription drug costs for payers as well for the patients.