Purpose: To determine whether prophylactic inhaled heparin is effective for the prevention and treatment of pneumonia patients receiving mechanical ventilation (MV) in the intensive care unit. Methods: A phase 2, double blind randomized controlled trial stratified for study center and patient type (nonoperative, post-operative) was conducted in three university-affiliated intensive care units. Patients aged ≥18 years and requiring invasive MV for more than 48 hours were randomized to usual care, nebulization of unfractionated sodium heparin (5000 units in 2 mL) or placebo nebulization with 0.9% sodium chloride (2 mL) four times daily with the main outcome measures of the development of ventilator associated pneumonia (VAP), ventilator associated complication (VAC) and sequential organ failure assessment scoresin patientswith pneumonia on admission or who developed VAP. Trial Registration: Australian and New Zealand Clinical Trials Registry ACTRN12612000038897. Results: Two hundred and fourteen patients were enrolled (72 usual care, 71 inhaled sodium heparin, 71 inhaled sodium chloride). There were no differences between treatment groups in terms of the development of VAP, using either Klompas criteria (6–7%, P = 1.00) or clinical diagnosis (24–26%, P = 0.85). There was no difference in the clinical consistency (P = 0.70), number (P = 0.28) or the total volume of secretions per day (P = .54). The presence of blood in secretions was significantly less in the usual care group (P = 0.005). Conclusion: Nebulized heparin cannot be recommended for prophylaxis against VAP or to hasten recovery from pneumonia in patients receiving MV.