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Infective endocarditis is a potentially fatal consequence of illicit injection drug use. We estimate that the number of hospitalization for injection drug use-related infective endocarditis increased by 38%–66% in the United States between 2000–2001 and 2002–2003, a period during which the number of at-risk persons (i.e., injection drug users) remained stable. Increasing methamphetamine use and/or drug injection frequency may have increased the incidence of infective endocarditis among active injection drug users.