OBJECTIVES: Polypharmacy, defined as concurrent use of six or more medications, is a critical issue in individuals with multiple chronic physical conditions. The objective of the study is to estimate the rates and types of drug use and hence polypharmacy among individuals with multiple chronic physical conditions and compare these to individuals without multimorbidity. We also examine the relationship between polypharmacy and various clusters of conditions to identify the trends of polypharmacy in particular clusters of conditions. METHODS: Cross-sectional analysis of 9259 individuals of age above 21, with at least one chronic physical condition in the following clusters: cardio-metabolic consisting of diabetes or heart disease or hypertension, respiratory consisting of chronic obstructive pulmonary disease or asthma and musculoskeletal consisting of osteoarthritis or rheumatoid arthritis or osteoporosis from the 2008 Medical Expenditure Panel Survey (MEPS).  Chi-square tests and multivariate logistic regressions were performed to analyze the rates and types of drug use and hence polypharmacy among various chronic clusters.  All analysis accounted for the complex survey design of the MEPS. RESULTS: In our study sample, 25.4% were on polypharmacy, and 75% reported use of 0 to 5 drugs.  In the multivariate model, individuals with either one or two clusters of conditions were significantly less likely to be on polypharmacy than those with multimorbidity with all the three clusters.  The adjusted odds ratio (AOR) ranged from 0.06 to 0.69.  Compared to individuals with multimorbidity with two clusters (respiratory and musculoskeletal), individuals without multimorbidity were as likely to be on polypharmacy.  Also polypharmacy varied with the type of cluster of conditions in another multivariate model, being more prominent in individuals with cardio-metabolic cluster of conditions. CONCLUSIONS: Polypharmacy varies with the type of cluster of conditions.  Our findings suggest that there is a higher medication burden in individuals with multimorbidity with at least one cardio-metabolic condition.