In an earlier neonatal porcine model of smoke inhalation injury (SII), immediate postinjury application of partial liquid ventilation (PLV) had dramatic beneficial effects on lung compliance, oxygenation, and survival over a 24-h period. To explore the efficacy of PLV following SII, we treated animals at 2 and 6 h after SII and followed them for 72 h. Pigs weighing 8-12 kg were sedated and pharmacologically paralyzed, given a SII, and placed on volume-cycled, pressure-limited ventilation. Animals were randomized to three groups: group I (+SII, no PLV, n = 8), group II (+SII, PLV at 2 h, n = 6), and group III (+SII, PLV at 6 h, n = 7). Ventilatory parameters and arterial blood gasses were obtained at scheduled intervals. The PLV animals (groups II and III) followed a worse course than group I (no PLV); PLV groups had higher peak and mean airway pressures, oxygenation index, and rate-pressure product (a barotrauma index) and lower lung compliance and arterial partial pressure of oxygen-to-inspired oxygen fraction ratio (all P < 0.05). PLV conferred no survival advantage. The reported beneficial effects of PLV with other models of acute lung injury do not appear to extend to the treatment of SII when PLV is instituted in a delayed manner. This study was not able to validate the previously reported beneficial effects of PLV in SII and actually found deleterious effects, perhaps reflecting the predominance of airway over alveolar disease in SII.