Background: N-acetylcysteine as a mucolytic agent is prescribed in different methods, in the patients who under mechanical ventilation. This study was designed to evaluate the effects of different methods of N-acetylcystein prescription in these patients.   Methods: In this randomized double blind clinical trial study, sixty CVA patients with mechanical ventilation were divided into three groups. Each group received 200 mg of N-acetylcysteine three times per day. Respiratory parameters such as dynamic compliance, rapid shallow breathing index (RSBI), the number of tracheal tube exchange and the number of tracheal tube suctioning were evaluated in all groups. Findings: Demographic variables were similar in all groups. Dynamic compliance was greater in intravenous than intragastric and intratracheal methods respectively (p <0.05). RSBI was lower in intravenous than intragastric and intratracheal methods respectively (p < 0.05). Intragastric method had higher number of tracheal tube exchange than intratracheal method and IV method has the lowest instance (p < 0.05). The IV method has the lowest number of tracheal tube suctioning than intragastric and intracheal methods respectively (p < 0.05). Conclusion: It seems that in the patients with mechanical ventilation, IV prescription of N-acetylcysteine has more advantages in comparison with intragastric and intratracheal methods . Key words: N-acetylcysteine, mechanical ventilation,dynamic compliance, rapid shallow breathing index, mucolytic agents.