We hypothesized that partial liquid ventilation (PLV) with perflubron in spontaneously breathing lung-injured animals would increase respiratory workload compared to animals treated with gas ventilation (GV), and that a fully synchronized mode, assist-control ventilation (AC), would reduce the piglets' effort when compared to intermittent mandatory ventilation (IMV) or synchronized IMV (SIMV) during both GV and PLV. Newborn piglets with saline lavage-induced lung injury were randomized to sequential 30-min periods of IMV --> SIMV --> AC (n = 5), or AC --> SIMV --> IMV (n = 5) during GV followed by PLV. Pulmonary mechanics measurements and an esophageal patient effort index (PEI, defined as the product of the area below baseline of the esophageal pressure-time curve and respiratory rate [RR]) were determined to estimate the patient's nonmechanical work of breathing, using a computer-assisted lung mechanics analyzer. GV to PLV comparisons showed no change in PEI (IMV, 57.8 vs. 49.7; SIMV, 52.3 vs. 46.8; AC, 15.7 vs. 13.7 cm H2O x s/min); intermode comparisons showed significantly decreased PEI in AC vs. IMV and SIMV during GV, and in AC vs. SIMV (AC vs. IMV, P = 0.06) during PLV. AC consistently resulted in the highest minute ventilation, lowest total respiratory rate, most physiologic pH, and least tidal volume variability. These observations suggest that synchronization with AC during GV and PLV may have substantial physiologic benefits.