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We investigated whether nonmedical opioid pain reliever use is associated with higher mortality in the general US population.We assessed the history of nonmedical opioid pain reliever use among 9985 people interviewed at baseline of the Epidemiologic Catchment Area Program initiated in 1981 to 1983 in Baltimore, Maryland; St. Louis, Missouri; and Durham, North Carolina. We linked the data with the National Death Index through 2007.Nonmedical opioid pain reliever use was 1.4%. Compared with no nonmedical drug use, mortality was increased for nonmedical opioid pain reliever use (hazard ratio [HR] = 1.60; 95% confidence interval [CI] = 1.01, 2.53) or nonmedical use of other drugs (HR = 1.31; 95% CI = 1.07, 1.62). Mortality was also higher for males and for those beginning nonmedical opioid pain reliever use before aged 15 years.A history of nonmedical opioid pain reliever use was associated with increased mortality, in particular for males and early onset users.