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Drotrecogin alfa was a landmark drug for treatment of severe sepsis, yet little is known about how it was adopted and de-adopted during its 10-year period of availability.We used hospitalization data on fee-for-service Medicare beneficiaries from 2002 to 2011 to characterize trends in the use of drotrecogin alfa in the United States.Drotrecogin alfa use peaked at 5.87 per 1000 severe sepsis hospitalizations in 2003 and then steadily declined to 0.94 administrations per 1000 severe sepsis hospitalizations in 2010. Large teaching hospitals were more likely to use drotrecogin alfa than small, nonteaching hospitals. The addition of “add-on payments” to hospitals for using drotrecogin alfa in 2002 was associated with significantly increased use (P < .0001), and the withdrawal of those payments in 2004 was associated significantly decreased use (P < .0001). Neither the publication of international sepsis guidelines with favorable drotrecogin alfa recommendations (in 2004 and 2008) nor the publication of a clinical trial focused on drotrecogin alfa (in 2005) were associated with consistent changes use (P > .05).Drotrecogin alfa use declined over time, with marked changes in use associated with drug-specific financial incentives but not the publication of clinical practice guidelines or clinical trials.