BACKGROUND Ventilator-associated pneumonia is associated with increased morbidity and mortality. OBJECTIVE To examine the effects of mechanical (toothbrushing), pharmacological (topical oral chlorhexidine), and combination (toothbrushing plus chlorhexidine) oral care on the development of ventilator-associated pneumonia in critically ill patients receiving mechanical ventilation. METHODS Critically ill adults in 3 intensive care units were enrolled within 24 hours of intubation in a randomized controlled clinical trial with a 2 x 2 factorial design. Patients with a clinical diagnosis of pneumonia at the time of intubation and edentulous patients were excluded. Patients (n = 547) were randomly assigned to 1 of 4 treatments: 0.12% solution chlorhexidine oral swab twice daily, toothbrushing thrice daily, both toothbrushing and chlorhexidine, or control (usual care). Ventilator-associated pneumonia was determined by using the Clinical Pulmonary Infection Score (CPIS). RESULTS The 4 groups did not differ significantly in clinical characteristics. At day 3 analysis, 249 patients remained in the study. Among patients without pneumonia at baseline, pneumonia developed in 24% (CPIS >or=6) by day 3 in those treated with chlorhexidine. When data on all patients were analyzed together, mixed models analysis indicated no effect of either chlorhexidine (P = .29) or toothbrushing (P = .95). However, chlorhexidine significantly reduced the incidence of pneumonia on day 3 (CPIS >or=6) among patients who had CPIS <6 at baseline (P = .006). Toothbrushing had no effect on CPIS and did not enhance the effect of chlorhexidine. CONCLUSIONS Chlorhexidine, but not toothbrushing, reduced early ventilator-associated pneumonia in patients without pneumonia at baseline.