Ventilator-associated pneumonia (VAP) is a type of hospital-acquired pneumonia that develops after more than 48 hours of mechanical ventilation Aim: To reveal the efficacy of combined parenteral and inhaled Colistin versus systemic Colistin in treatment of critical ill patients with multidrug and extensive drug resistant Ventilator Associated Pneumonia Patients and methods: This study was conducted on 60 patients meeting the criteria for ventilator associated pneumonia. They divided into group I: consisted of 30 patients subjected to the combined systemic and inhalational Colistin treatment & group II: included the remaining 30 patients subjected to the systemic treatment only. Patients were admitted to International Medical Center and Cairo University Hospitals over a period of two years starting from October 2020 to October 2022. Results: Overall resolution of VAP was superior in the combined group (12 patients) (40%) in comparison to the IV only group (9 patients) (30%). Concerning in hospital mortality, 12 patients from the combined group (40%), and 16 patients from the IV group (53.3%) died (P value = 0.301). Successful weaning of MV of 18 patients (60%) for the combined group, and was 46.7% (14 patients) for the IV group Conclusion: Combined inhaled and systemic colistin administration resulted in faster weaning of MV and resolution of pneumonia, no significant differences were found regarding mortality or overall length of ICU stay. Inhaled colistin provides direct drug depositions to the infection site, reducing systemic exposure, increasing antimicrobial efficacy and reduceing nephrotoxicity and neurotoxicity.