Background: Mechanical ventilation is a lifesaving procedure that is indicated for critically ill patients. Clinical decision making in nursing practice is a complex process that is integrated into the nursing profession. Critical care nurses are continually faced with situations where they have to make knowledgeable decisions. Purpose: To identify the relationship between critical care nurses' knowledge and clinical decision making role in managing mechanically ventilated patients. Research Design: A descriptive correlational research design was used in this study. Setting: The study was conducted at intensive care units in Nasser Institute. Sample: A purposive sample of 109 critical care nurses were selected. Instruments: Data was collected using three instruments (critical care nurses' characteristics structured questionnaire, critical care nurses' knowledge structured interview questionnaire, and clinical decision making in nursing scale (CDMNS)). Results: The majority of the studied sample (95.4%) had a satisfactory level of knowledge about caring for patients on mechanical ventilation, more than two thirds of the studied sample (73.4%) had moderate insight of decision making role. There is a statistical significant positive correlation between total decision making and general information about, communication, checking ventilator settings and modes, standard care for endotracheal suction, and management of ventilator alarm. Conclusion: There is a positive correlation between nurses' knowledge and clinical decision making role. Recommendations: The principles of mechanical ventilation must be explained and incorporated into interactive training programs, Training courses regarding clinical decision making for critical care nurses must be provided. Replication of the same study on larger probability samples at different geographical locations for data generalization.