OBJECTIVE To evaluate efficacy of an alveolar recruitment maneuver (ARM) with positive end-expiratory pressures (PEEPs) in anesthetized horses ventilated with oxygen or heliox (70% helium and 30% oxygen). ANIMALS 6 healthy adult horses. PROCEDURES In a randomized crossover study, horses were anesthetized and positioned in dorsal recumbency. Volume-controlled ventilation was performed with heliox or oxygen (fraction of inspired oxygen [F_io2] > 90%). Sixty minutes after mechanical ventilation commenced, an ARM with PEEP (0 to 30 cm H₂O in steps of 5 cm H₂O every 5 minutes, followed by incremental steps back to 0 cm H₂O) was performed. Peak inspiratory pressure, dynamic lung compliance (C_dyn), and Pa_o2 were measured during each PEEP. Indices of pulmonary oxygen exchange and alveolar dead space were calculated. Variables were compared with baseline values (PEEP, 0 cm H₂O) and between ventilation gases by use of repeated-measures ANOVAs. RESULTS For both ventilation gases, ARM significantly increased pulmonary oxygen exchange indices and C_dyn. Mean ± SD C_dyn (506 ± 35 mL/cm H₂O) and Pa_o2-to-F_io2 ratio (439 ± 36) were significantly higher and alveolar-arterial difference in Pa_o2 (38 ± 11 mm Hg) was significantly lower for heliox, compared with values for oxygen (357 ± 50 mL/cm H₂O, 380 ± 92, and 266 ± 88 mm Hg, respectively). CONCLUSIONS AND CLINICAL RELEVANCE An ARM in isoflurane-anesthetized horses ventilated with heliox significantly improved pulmonary oxygen exchange and respiratory mechanics by decreasing resistive properties of the respiratory system and reducing turbulent gas flow in small airways.