Background Many patients each year require prolonged mechanical ventilation. Inflammatory processes may prevent successful weaning, and evidence indicates that mechanical ventilation induces oxidative stress in the diaphragm, resulting in atrophy and contractile dysfunction of diaphragmatic myofibers. Antioxidant supplementation might mitigate the harmful effects of the oxidative stress induced by mechanical ventilation. Objective To test the clinical effectiveness of antioxidant supplementation in reducing the duration of mechanical ventilation. Methods A randomized, prospective, placebo-controlled double-blind design was used to test whether enterally administered antioxidant supplementation would decrease the duration of mechanical ventilation, all-cause mortality, and length of stay in the intensive care unit and hospital. Patients received vitamin C 1000 mg plus vitamin E 1000 IU, vitamin C 1000 mg plus vitamin E 1000 IU plus N -acetylcysteine 400 mg, or placebo solution as a bolus injection via their enteral feeding tube every 8 hours. Results Clinical and statistically significant differences in duration of mechanical ventilation were seen among the 3 groups (Mantel-Cox log rank statistic = 5.69, df = 1, P = .017). The 3 groups did not differ significantly in all-cause mortality during hospitalization or in the length of stay in the intensive care unit or hospital. Conclusions Enteral administration of antioxidants is a simple, safe, inexpensive, and effective intervention that decreases the duration of mechanical ventilation in critically ill adults.