Introduction: Little is known about how combinations of chronic conditions in adults affect total health care expenditures. Our objective was to estimate the annual average total expenditures and out-of-pocket spending burden among US adults by combinations of conditions. Methods: We conducted a cross-sectional study using 2009 and 2011 data from the Medical Expenditure Panel Survey. The sample consisted of 9,296 adults aged 21 years or older with at least 2 of the following 4 highly prevalent chronic conditions: arthritis, diabetes mellitus, heart disease, and hypertension. Unadjusted and adjusted regression techniques were used to examine the association between chronic condition combinations and log-transformed total expenditures. Logistic regressions were used to analyze the relationship between chronic condition combinations and high out-ofpocket spending burden. Results: Among adults with chronic conditions, adults with all 4 conditions had the highest average total expenditures ($20,016), whereas adults with diabetes/hypertension had the lowest annual total expenditures ($7,116). In adjusted models, adults with diabetes/ hypertension and hypertension/arthritis had lower health care expenditures than adults with diabetes/heart disease (P < .001). In adjusted models, adults with all 4 conditions had higher expenditures compared with those with diabetes and heart disease. However, the difference was only marginally significant (P = .04). Conclusion: Among adults with arthritis, diabetes, heart disease, and hypertension, total health care expenditures differed by type of chronic condition combinations. For individuals with multiple chronic conditions, such as heart disease and diabetes, new models of care management are needed to reduce the cost burden on the payers.