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This study was performed to determine if prolonged mechanical ventilation (MV) could be predicted by objective clinical variables present at 48 hours after MV was instituted. During a 3-month period, 49 (54%) of 91 mechanically ventilated surgical intensive care unit patients required MV for 2 or more days. Twelve (24%) of these patients died. Patients requiring 2–13 days of MV had significantly lower alveolar-arterial oxygen gradients (PAO2 — Pao2), PEEP, and Fio2 on MV day 2 compared with patients with MV ≥14 days. PAO2 - Pao2 >175 mm Hg on day 2 in patients without chronic obstructive pulmonary disease (COPD) was 60% sensitive and 91% specific for MV ≥14 days. In survivors, a day-2 PAO2 - Pao2 ≥175 mm Hg (without COPD) or a GCS score ≤9 had a 91% positive predictive value and a 96% negative predictive value for MV ≥14 days. We conclude that mechanical ventilation for 14 or more days can be accurately predicted at 48 hours after the institution of ventilatory support by these objective criteria.