OBJECTIVES: Prior studies have demonstrated increasing Clostridium difficile infections (CDI) in United States (U.S.) hospitals; however, it is unknown if regional or seasonal differences exist. This study identifies regional and seasonal variations in CDI incidence and mortality among hospitalized adults over a ten-year period. METHODS: This was a retrospective analysis of the U.S. National Hospital Discharge Surveys from 2001 to 2010. Eligible cases included adults ≥18 years of age with an ICD-9-CM diagnosis code for CDI (008.45). Data weights were used to derive national estimates. Mortality and CDI incidence were presented descriptively. CDI incidence rates were calculated as CDI discharges per 1,000 total adult discharges. Regions included the Northeast, Midwest, South, and West as defined by the U.S. Census Bureau. Seasons included: Winter (December-February), Spring (March-May), Summer (June-August), and Fall (September-November). RESULTS: These data represent 2.2 million adult CDI discharges. CDI incidence was highest in the Northeast (9.2 CDI discharges/1,000 total discharges), followed by the Midwest (7.4 CDI discharges/1,000 total discharges), South (5.9 CDI discharges/1,000 total discharges), and West (5.7 CDI discharges/1,000 total discharges). Rates increased in all regions through 2008. Although, rates declined in the Northeast, Midwest, and West since 2008, rates in the South continued to increase until study end. CDI incidence was highest in the Spring (7.2 CDI discharges/1,000 total discharges), followed by the Summer (6.9 CDI discharges/1,000 total discharges), Winter (6.8 CDI discharges/1,000 total discharges), and Fall (6.6 CDI discharges/1,000 total discharges). Rates increased in all seasons over the study period, but have declined in the Fall since 2008. Mortality among CDI patients was highest in the Midwest (7.5%) and during the Winter (8.5%). CONCLUSIONS: CDI increased for all regions over the study period, and was highest in the Northeast. Peak CDI incidence occurred in the Spring, but mortality was highest in the Winter.