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Aim. The purpose of this study was to examine the effect of acupressure on anxiety in patients under mechanical ventilation. Background. Mechanical ventilation is a frequently used technological modality for patients in Intensive Care Unit (ICU), and this treatment has potential to produce a variety of unpleasant stress and physiological and psychological complications. Anxiety is one of the most common mental reactions in patients under mechanical ventilation. Acupressure as a non-pharmacological approach may improve anxiety in these patients without side effects. Method. This was a randomized block experimental study in which 164 ventilated patients with stable hemodynamics and GCS≥9 who had study criteria were randomly allocated into experimental or control group. Patients in the experimental group received two sessions/day of acupressure along with routine care for two consecutive days, but patients in the control group received only routine care. The anxiety was measured with Faces Anxiety Scale (FAS), before, right after, and one hour following every acupressure session. The data were analyzed by SPSS software using descriptive and inferential statistics. Findings. Baseline anxiety level was high in most of patients. Anxiety in the experimental group decreased significantly (p=0.032) when compared with control group, over time. Anxiety was significantly different between groups, right after intervention in every session of acupressure (p<0.0001). In the experimental group, time-dependent changes of anxiety was statistically significant (p<0.0001) and anxiety was significantly different before and right after intervention in every session of acupressure (p<0.0001). The amount of change in anxiety was not significantly different between sessions. Conclusion. Acupressure therapy could reduce anxiety significantly in patients with mechanical ventilation. Critical care nurses can use this non-pharmacological approach to reduce anxiety in patients under mechanical ventilation.