BACKGROUND Emerging evidence suggests that the prevalence of pathogens common in cystic fibrosis (CF) may be unevenly distributed across the United States (U.S.). However, very little is known regarding the U.S. distribution of other CF modifiers such as medication usage and patient demographics. Therefore, we sought to determine if regional differences exist in the distribution of demographic variables and patient disease characteristics in the U.S. that may play a role in differential CF outcomes. METHODS Data were analyzed from the 30,896 subjects in the U.S. CF Foundation Patient Registry during the years 2007-2012, via geographical grouping of states based upon the Nationwide Inpatient Sample classification. RESULTS Significant differences in racial distribution were seen, including half of the total U.S. African-American CF population residing in the South. Both African-Americans and Hispanics had increased Medicaid usage (52.2%, 41.8%, respectively). Culture-reported pathogens were markedly different across the U.S., with the highest percentage of patients with Methicillin-resistant Staphylococcus aureus (41.9%), Pseudomonas aeruginosa (71.2%), and non-tuberculous mycobacterium (10.0%) in the South. The South region also had the lowest mean body mass index and forced expiratory volume in one second. Chronic medication usage such as inhaled tobramycin or macrolides followed P. aeruginosa distribution, while inhaled dornase alfa was most used in the West (84.7%). Co-morbid conditions varied, with the highest percentage of depressed subjects in the Midwest (18.3%). Mean regional mortality rates were not statistically different among regions, although highest in each age grouping of the South. CONCLUSIONS The U.S. has significant regional variations in CF demographics, insurance, pathogens, medication usage, and co-morbidities, without an overall impact on regional mortality. Regional variations in care practices should be studied further based on the findings.