Noninvasive and invasive diagnostic techniques have been shown to achieve comparable performances in the evaluation of suspected ventilator-associated pneumonia (VAP). We studied the impact of both approaches on outcome in a prospective, open, and randomized study in three intensive care units (ICUs) of a 1,000-bed tertiary care university hospital. Patients with suspected VAP were randomly assigned to noninvasive (Group 1) versus invasive (Group 2) investigation (tracheobronchial aspirates [TBAS] versus bronchoscopically retrieved protected specimen brush [PSB] and bronchoalveolar lavage [BAL]. Samples were cultured quantitatively, and BAL fluid (BALF) was examined for intracellular organisms (ICO) additionally. Initial empiric antimicrobial treatment was administered following the guidelines of the American Thoracic Society (ATS) and adjusted according to culture results (and ICO counts in Group 2). Outcome variables included length of ICU stay and mechanical ventilation as well as mortality. Overall, 76 patients (39 noninvasive, 37 invasive) were investigated. VAP was microbiologically confirmed in 23 of 39 (59%) and 23 of 37 (62%) (p = 0.78). There were no differences with regard to the frequencies of community-acquired and potentially drug-resistant microorganisms (PDRM). Antimicrobial treatment was changed in seven patients (18%) of Group 1 and 10 patients (27%) of Group 2 because of etiologic findings (including five of 17 with ICO = 2% (p = not significant [NS]). Length of ICU stay and mechanical ventilation were also not significantly different in both groups. Crude 30-d mortality was 31 of 76 (41%), and 18 of 39 (46%) in Group 1 and 14 of 37 (38%) in Group 2 (p = 0.46). Adjusted mortality was 16% versus 11% (p = 0.53), and mortality of microbiologically confirmed pneumonia 10 of 23 (44%) in both groups (p = 1.0). We conclude that the outcome of VAP was not influenced by the techniques used for microbial investigation.