Background: Mechanical ventilator (MV) is a potential life-saving machine. However, receiving MV may create a discomfort experience, especially for conscious patients. This condition can be related to several circumstances such as pain and gagging from the endotracheal tube, sleep disturbance and inability to communicate. Therefore, nurses need to provide an appropriate nursing care program for mechanically ventilated patients in reducing discomfort and improving comfort. Objective: This article aimed to present an exemplar of implementation of an innovative nursing program for relieving discomfort in mechanically ventilated patients from the experience in practice. Methods: Updated evidence-based practice to develop innovative nursing care program to relieve discomfort in MV patients were reviewed, analyzed and synthesized following the recommendation of The Joanna Briggs Institute for Evidence-Based Nursing. The innovative program was divided into six subprograms: 1) suctioning; 2) thirsty and dry mouth; 3) communication ability, 4) sleep disturbance; 5) limited movement; and 6) emotional discomfort. Before implementation, the program was proposed to the nurses in two medical wards and one medical intensive care unit to adjust the program to fit with contexts of the settings. Four patients who met the inclusion criteria were recruited for the program for three days. The level of discomfort and factors related to discomfort were assessed before and after the intervention. Results: The level of discomfort on the first day before implementing the program was in the moderate level. Three common causative factors of discomfort were come from suctioning, thirst and dry mouth and difficulty in communication. The result showed that the level of discomfort on the third day after receiving the program had decreased from the first day. Conclusion and Recommendation: From the authors' experience of the implementation of this innovative program in four patients, this program is an effective program to relieve patients discomfort during receiving MV. The program can be recommended to the nurses to be applied in practice. In addition, this exemplar confirmed that providing nursing care based on the evidences produced the good outcome of care. Nurses can improve and update their nursing care by valuing evidence-based practice as guided by this experience.