Abstract Background An endotracheal tube cuff pressure between 20 and 30 cmH2O is recommended to prevent ventilator-associated respiratory infection (VARI). We aimed to evaluate whether continuous cuff pressure control (CPC) was associated with reduced VARI incidence compared with intermittent CPC. Methods We conducted a multicenter open-label randomized controlled trial in intensive care unit (ICU) patients within 24 hours of intubation in Vietnam. Patients were randomly assigned 1:1 to receive either continuous CPC using an automated electronic device or intermittent CPC using a manually hand-held manometer. The primary endpoint was the occurrence of VARI, evaluated by an independent reviewer blinded to the CPC allocation. Results We randomized 600 patients; 597 received the intervention or control and were included in the intention to treat analysis. Compared with intermittent CPC, continuous CPC did not reduce the proportion of patients with at least one episode of VARI (74/296 25% vs 69/301 23%; odds ratio OR 1.13; 95% confidence interval CI .77–1.67. There were no significant differences between continuous and intermittent CPC concerning the proportion of microbiologically confirmed VARI (OR 1.40; 95% CI .94–2.10), the proportion of intubated days without antimicrobials (relative proportion RP 0.99; 95% CI .87–1.12), rate of ICU discharge (cause-specific hazard ratio HR 0.95; 95% CI .78–1.16), cost of ICU stay (difference in transformed mean DTM 0.02; 95% CI −.05 to .08, cost of ICU antimicrobials (DTM 0.02; 95% CI −.25 to .28), cost of hospital stay (DTM 0.02; 95% CI −.04 to .08), and ICU mortality risk (OR 0.96; 95% CI .67–1.38). Conclusions Maintaining CPC through an automated electronic device did not reduce VARI incidence. Clinical Trial Registration NCT02966392. The results of this randomised controlled trial demonstrate that continuous endotracheal cuff pressure control using an electronic automated device does not reduce the occurrence of ventilator-associated respiratory infection (VARI) in intubated patients compared with intermittent control.