In order to assess potential risk factors for pneumonia within the first 8 d of ventilation, we studied 83 consecutive intubated patients undergoing continuous aspiration of subglottic secretions (CASS). Multivariate analysis showed the protective effect of antibiotic use (relative risk [RR] = 0.10; 95% confidence interval [CI] = 0.01 to 0.71), whereas failure of the CASS technique (RR = 5.29; 95% CI = 1.24 to 22.64) was associated with a greater risk of pneumonia. In addition, there was a trend toward a higher risk of pneumonia (RR = 2.57; 95% CI = 0.78 to 8.03) among patients with persistent intracuff pressures below 20 cm H2O. The remaining factors analyzed were not significant. Failure of CASS did not influence the development of pneumonia among patients undergoing antibiotic treatment (33.0% versus 38.5%, p > 0.20), but was strongly associated with pneumonia (42.1% versus 8.3%, p < 0.01) among intubated patients not receiving antibiotics. When multivariate analysis was repeated in this subpopulation, failure of CASS (RR = 7.52, 95% CI = 1.48 to 38.07) and persistent intracuff pressure below 20 cm H2O (RR = 4.23, 95% CI = 1.12 to 15.92) were factors independently associated with the development of pneumonia. We conclude that leakage of colonized subglottic secretions around the cuff of the endotracheal tube is the most important risk factor for pneumonia within the first 8 d of intubation. This study confirms the importance of maintaining adequate intracuff pressure and effective aspiration of subglottic secretions in preventing pneumonia in intubated patients not receiving antibiotic treatment.