Background Clostridium difficile infection (CDI) incidence is a growing concern. This study provides national estimates of CDI over 10 years and identifies trends in mortality and hospital length of stay (LOS) among hospitalized adults with CDI. Methods We conducted a retrospective analysis of the US National Hospital Discharge Surveys from 2001-2010. Eligible cases included adults aged ≥18 years discharged from a hospital with an ICD-9-CM diagnosis code for CDI (008.45). Data weights were used to derive national estimates. CDI incidence rates were depicted as CDI discharges per 1,000 total adult discharges. Results These data represent 2.2 million adult hospital discharges for CDI over the study period. CDI incidence increased from 4.5 CDI discharges per 1,000 total adult discharges in 2001 to 8.2 CDI discharges per 1,000 total adult discharges in 2010. The overall in-hospital mortality rate was 7.1% for the study period. Mortality increased slightly over the study period, from 6.6% in 2001 to 7.2% in 2010. Median hospital LOS was 8 days (interquartile range, 4-14 days), and remained stable over the study period. Conclusions The incidence of CDI among hospitalized adults in the United States nearly doubled from 2001-2010. Furthermore, there is little evidence of improvement in patient mortality or hospital LOS.