Ventilator-associated pneumonia (VAP) increases length of stay (LOS) in VAP versus non-VAP patients, but LOS differences among VAP patients remain unexplained. We explored the economic impact of developing a respiratory superinfection while being treated for VAP. This was a retrospective, observational cohort study conducted in 74 patients discharged between January 2004 and July 2005 identified as having VAP. Using detailed, chart-abstracted demographic and hospital-course data--including antibiotic therapy, APACHE II scores, and superinfection development--multivariable analysis determined variables independently associated with LOS and total accounting costs from the date of VAP identification (VAP ID) to discharge or death. Overall mortality and mean +/- SD APACHE II were 35% and 19.4 +/- 8.9 for 74 cases; 35% of the cohort developed a superinfection. Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella spp. were most frequently responsible. Mortality was unaffected by superinfection. Younger age (P = 0.003), superinfection (P = 0.006), and admission to the surgical intensive care unit (ICU) (P = 0.014) independently predicted LOS (adjusted R(2) = 0.296). Younger age (P < 0.001), admission to the surgical ICU (P = 0.004), superinfection (P = 0.002), and previous antibiotic exposure (P = 0.009) predicted increased costs (adjusted R(2) = 0.394). Mean (95% CI) LOS and total costs after contracting VAP were greater for superinfection patients [47.8 days (39.0 to 56.5) versus 27.9 (22.4 to 33.1), P < 0.001; $140,850 ($98,426 to $183,275) versus $73,801 ($58,946-$88,656), P < 0.001], with 15.6 days and $48,527 attributable to superinfection. While not affecting mortality in those patients with VAP, superinfections independently predict increased LOS after VAP ID, contributing to substantial additional cost.