The treatment of acute respiratory failure in infants by means of extracorporeal membrane oxygenation (ECMO) is thought to be associated with a treatment-related inflammatory reaction, which may deteriorate the underlying disease process. The aim of this study was to compare the venoarterial (VA) and venovenous (VV) modality of ECMO with regard to their pulmonary and serological cytokine release during rescue from acute hypoxia. The inflammatory response was measured in piglets undergoing hypoxic ventilation with a gas mixture of 92% N2 and 8% O2, which were then rescued through VA- (n = 5) or VV-ECMO (n = 5). The effect of cannulation and anesthesia on the inflammatory response was deducted from regularly ventilated control animals (n = 5). The concentrations of the proinflammatory interleukins (IL)-1beta and IL-8 increased in the bronchoalveolar lavage fluid of all groups over a study period of 5 h but were significantly higher (P < 0.05) during VA-ECMO treatment, whereas the anti-inflammatory IL-10 concentrations were significantly higher in the bronchoalveolar lavage fluid of VV-treated animals (P < 0.001). No statistical difference between groups was found in the serum concentrations of cytokines. We conclude that in this animal model rescue from hypoxia by means of the VA modality of ECMO leads to a more pronounced inflammatory reaction of the lung than when applying the VV modality.