BackgroundMultimorbidity is common, but the prevalence and burden of the specific combinations of coexisting disease has not been systematically examined in the general U.S. adult population. ObjectiveTo identify and estimate the burden of highly prevalent combinations of chronic conditions that are treated among one million or more adults in the United States. MethodsCross-sectional analysis of U.S. households in the Medical Expenditure Panel Survey (MEPS), 2016-2019, a large nationally-representative sample of the community-dwelling population. Association rule mining was used to identify the most common combinations of 20 chronic conditions that have high relevance, impact, and prevalence in primary care. The main measures and outcomes were annual treated prevalence, total medical expenditures, and perceived poor health. Logistic regression models with poor health as the outcome and each multimorbidity combination as the exposure were used to calculate adjusted odds ratios and 95% confidence intervals. ResultsFrequent pattern mining yielded 223 unique combinations of chronic disease, including 74 two-way (dyad), 115 three-way (triad), and 34 four-way combinations that are treated in one million or more U.S. adults. Hypertension-hyperlipidemia was the most common two-way combination occurring in 30.8 million adults. The combination of diabetes-arthritis-cardiovascular disease was associated with the highest median annual medical expenditures ($23,850, interquartile range: $11,593-$44,616), and the combination of diabetes-arthritis-asthma/COPD had the highest age-race-sex adjusted odds ratio of poor self-rated health (adjusted odd ratio: 6.9, 95%CI: 5.4-8.8). ConclusionThis study demonstrates that many multimorbidity combinations are highly prevalent among U.S. adults, yet most research and practice-guidelines remain single disease focused. Highly prevalent and burdensome multimorbidity combinations could be prioritized for evidence-based research on optimal prevention and treatment strategies.