Background:: Intellivent is a new full closed-loop controlled ventilation that automatically adjusts both ventilation and oxygenation parameters. The authors compared gas exchange and breathing pattern variability of Intellivent and pressure support ventilation (PSV). Methods:: In a prospective, randomized, single-blind design crossover study, 14 patients were ventilated during the weaning phase, with Intellivent or PSV, for two periods of 24 h in a randomized order. Arterial blood gases were obtained after 1, 8, 16, and 24 h with each mode. Ventilatory parameters were recorded continuously in a breath-by-breath basis during the two study periods. The primary endpoint was oxygenation, estimated by the calculation of the difference between the Pao2/Fio2 ratio obtained after 24 h of ventilation and the Pao2/Fio2 ratio obtained at baseline in each mode. The variability in the ventilatory parameters was also evaluated by the coefficient of variation (SD to mean ratio). Results:: There were no adverse events or safety issues requiring premature interruption of both modes. The Pao2/Fio2 (mean ± SD) ratio improved significantly from 245 ± 75 at baseline to 294 ± 123 (P = 0.03) after 24 h of Intellivent. The coefficient of variation of inspiratory pressure and positive end-expiratory pressure (median [interquartile range]) were significantly higher with Intellivent, 16 [11–21] and 15 [7–23]%, compared with 6 [5–7] and 7 [5–10]% in PSV. Inspiratory pressure, positive end-expiratory pressure, and Fio2 changes were adjusted significantly more often with Intellivent compared with PSV. Conclusions:: Compared with PSV, Intellivent during a 24-h period improved the Pao2/Fio2 ratio in parallel with more variability in the ventilatory support and more changes in ventilation settings.