Risk factors for ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Gram-negative bacilli (CR-GNB) have rarely been evaluated in intensive care units (ICU) without epidemic carbapenemase-producing Acinetobacter baumannii or Enterobacteriaceae. We addressed this issue in a cohort of 141 patients (previous antimicrobial exposure, n = 131) with a first episode of VAP in a medico-surgical ICU. Twenty-six VAP (18.4%) involved a CR-GNB (Pseudomonas aeruginosa, n = 14, Stenotrophomonas maltophilia, n = 11, and A. baumannii, n = 1), without previous carbapenem exposure in 12 (46.1%) cases. GNB resistant to all β-lactams except carbapenems were equally isolated in CR-GNB VAP (co-infections, 23%) and other episodes (30%). Previous exposure to aminoglycosides (odds ratio (OR) 1.14 per day, 95% confidence interval (CI) 1.02-1.30, p = 0.02) and the number of antimicrobial classes used before VAP (OR 1.38 per class, 95% CI 1.10-1.73, p = 0.006) were the only independent predictors of CR-GNB. These results suggest that the empirical use of a carbapenem-colistin combination should be evaluated in late-onset VAP following broad-spectrum antimicrobial exposure.