OBJECTIVES:  The cystic fibrosis (CF) is a genetic disorder requiring medical care for whole lifespan. A previous study reported that an incremental medical care expenditure of CF was $45,927 (2006 US dollar) per person per year based on private insurance claims database. However, the national cost burden of CF remains unknown. This study aimed to examine the nationally representative direct cost burden of CF at individual and national levels. METHODS:  We conducted pooled cross-sectional analyses using 2010-2014 Medical Expenditure Panel Survey dataset. CF patients were identified with the ICD-9 code “277” from Medical Condition file. We employed multivariable two-part models consisting of logit and generalized linear model with log link and gamma distribution. The total expenditure was an outcome variable, summing up expenditures of office-based visit, outpatient visit, emergency department visit, inpatient visit and medication. Covariates included age, gender, race, marital status, education, family poverty level, insurance type, region and year. Adjusted incremental direct costs of CF were obtained compared to patients without CF. All costs were converted to 2014 US dollar using Medical Care components of Consumer Price Index. RESULTS:  The unweighted (weighted) sample sizes for CF and non-CF patients were 163 (423,202) and 163,430 (313,057,747), respectively. The weighted annual prevalence of CF was 1.35 per 1,000 persons. The incremental medical expenditure of CF was $11,283 (p=0.003) per person per year. The major contributor of incremental medical expenditure was medication expenditure ($2,783, p=0.034) followed by inpatient expenditure ($2,702, p=0.123) and office visits ($1,153, p=0.003). Total national medical expenditure was $955 million per year. CONCLUSIONS:  The direct cost burden of CF was considerable although it was lower than the case of privately insured population. Further research on indirect costs is necessary for CF patients.