Objectives Ventilator-associated pneumonia (VAP) is one of the most common nosocomial infections in intensive care units (ICUs), and the use of mouthwash is the most widely used method to prevent its incidence. The aim of this study was to investigate effect of clove mouthwash on the incidence of VAP in the ICU. Materials and methods This comparative, randomized, triple-blind, clinical trial was conducted on 168 eligible ICU patients at Kosar Hospital in Semnan, Iran, during 2021-2022, who were divided into intervention and control groups using random blocks. The intervention group received clove extract mouthwash at 6.66% concentration, and the control group received chlorhexidine 0.2% twice a day for 5 days (routine care). Data were collected using a demographic questionnaire, and disease severity was measured based on the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, oral health status was examined using the Beck Oral Assessment Scale (BOAS), and VAP diagnosis was made based on the Modified Clinical Pulmonary Infection Score (MCPIS). Results Before the intervention, there was no significant difference in disease severity (p = 0.412) and oral health status (p = 0.239) between the patients in the two groups. After the intervention, 20.2% of the patients in the intervention group and 41.7% of those in the control group acquired VAP. The risk of VAP was 2.06 times higher in the control group than in the intervention group (p = 0.005, 95% CI: 1.26-3.37, RR = 2.06), but the severity of VAP did not differ significantly between the patients in the two groups (p = 0.557). ConclusionThe findings showed that clove mouthwash reduces the incidence of VAP significantly. Clinical relevance Clove mouthwash can be used as a simple and low-cost method to prevent VAP in ICU patients.