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Although many studies have examined nosocomial bloodstream infection (BSI), US national estimates of incidence and case-fatality rates have seldom been reported.The purposes of this study were to generate US national estimates of the incidence and severity of nosocomial BSI and to identify risk factors for nosocomial BSI among adults hospitalized in the United States on the basis of a national probability sample.This cross-sectional study used the US Nationwide Inpatient Sample for the year 2003 to estimate the incidence and case-fatality rate associated with nosocomial BSI in the total US population. Cases of nosocomial BSI were defined by using 1 or more International Classification of Diseases, 9th Revision, Clinical Modification codes in the secondary field(s) that corresponded to BSIs that occurred at least 48 hours after admission. The comparison group consisted of all patients without BSI codes in their NIS records. Weighted data were used to generate US national estimates of nosocomial BSIs. Logistic regression was used to identify independent risk factors for nosocomial BSI.The US national estimated incidence of nosocomial BSI was 21.6 cases per 1,000 admissions, while the estimated case-fatality rate was 20.6%. Seven of the 10 leading causes of hospital admissions associated with nosocomial BSI were infection related. We estimate that 541,081 patients would have acquired a nosocomial BSI in 2003, and of these, 111,427 would have died. The final multivariate model consisted of the following risk factors: central venous catheter use (odds ratio [OR], 4.76), other infections (OR, 4.61), receipt of mechanical ventilation (OR, 4.97), trauma (OR, 1.98), hemodialysis (OR, 4.83), and malnutrition (OR, 2.50). The total maximum rescaled R2 was 0.22.The Nationwide Inpatient Sample was useful for estimating national incidence and case-fatality rates, as well as examining independent predictors of nosocomial BSI.