Background Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate-ribose) polymerase enzyme after massive DNA damage may aggravate inflammatory responses. Therefore, the authors hypothesized that the pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase by PJ-34 would attenuate ventilator-induced lung injury. Methods Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomly assigned to receive mechanical ventilation at either low tidal volume (6 ml/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (15 ml/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34. Results The high-tidal-volume ventilation resulted in an increase in poly(adenosine diphosphate-ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin 6, active plasminogen activator inhibitor 1 in the lung, attenuated leukocyte lung transmigration, and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor alpha and interleukin 6, and attenuated the degree of apoptosis in the kidney. Conclusion The pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.