The main causes of lung injury after cardiopulmonary bypass (CPB) are systemic inflammatory response syndrome (SIRS) and pulmonary ischaemia-reperfusion injury (IR-I). SIRS and IR-I are often initiated by a systemic inflammatory response. The present study investigated whether the annexin A1 (ANX-A1) peptidomimetic Ac2-26 by binding to formyl peptide receptors (FPRs) inhibit inflammatory cytokines and reduce lung injury after CPB. Male rats were randomized to the following five groups (n = 6, each): sham, exposed to pulmonary ischaemic-reperfusion (IR-I), IR-I plus Ac2-26, IR-I plus the FPR antagonist, BoC2 (N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe) and IR-I plus Ac2-26 and BoC2. Treatment with Ac2-26 improved the oxygenation index, an effect blocked by BoC2. Histopathological analysis of the lung tissue revealed that the degree of lung injury was significantly less (P < 0.05) in the Ac2-26-treated rats compared to the other experimental groups exposed to IR-I. Ac2-26 treatment reduced the levels of the inflammatory cytokines TNF-α, IL-1β, ICAM-1 and NF-κB-p65 (P < 0.05) compared to the vehicle-treated group exposed to IR-I. In conclusion, the annexin A1 (ANX-A1) peptidomimetic Ac2-26 by binding to formyl peptide receptors inhibit inflammatory cytokines and reduce ischaemic-reperfusion lung injury after cardiopulmonary bypass.