OBJECTIVES: To determine the economic impact of three different hospital-acquired infections (HAI) in mechanically ventilated (MV) patients in intensive care unit (ICU) and assess the attributable costs,  hospital length of stay (LOS) and inpatient mortality in a U.S. hospital database. METHODS: A U.S. retrospective cohort study was undertaken using hospital database from the Premier Perspective of adults (≥18 years old) with a stay ≥ 48h in 2007.  Three HAIs were followed: bloodstream infection (BSI), surgical site infection (SSI), and hospital-acquired pneumonia (HAP) including ventilator-associated pneumonia (VAP). From a previous analysis, MV device was identified as an impactful risk factor in ICU showing higher prevalence for HAP/VAP and BSI. Case subjects were defined as patients with HAI event among the MV population. Economic criteria were defined as hospital LOS, inpatient mortality and inpatient costs. RESULTS: Out of 463,491 patients meeting the entry criteria, 101,540 (21.9%) received a MV setting. Focusing on this MV population, 51,683 (50.9%) patients developed HAI: HAP/VAP: 33.2%, BSI: 29.4%, and SSI: 2.3%. Compared with control, patients with HAI were more elderly (54% vs. 49%), were more likely to be admitted via emergency room (86% vs. 78%), presented with more severe illnesses, higher risk of mortality, and with central catheter placements (67% vs. 39%). The inpatient mortality rate and mean LOS were higher in patients with HAI (32% vs. 18% and 21.2+22.3 vs. 11.8+11.4 days, respectively). Mean total costs were higher in HAI patients (56,751US$) compared to non-HAI patients (34,032US$). In MV population, HAI patients had higher consumptions of inpatient resources and inpatient mortality: extended LOS equal to 9.4 days, increased total inpatient costs equal to 22,719US$ and extended mortality of 14%. CONCLUSIONS: These data illustrate the significant economic burden and mortality of HAI in a category of at-risk population on MV and request the needs for intervention.