Introduction: Transplantation (Tx) is the only therapeutic option for the treatment of several lung diseases. However, ischemia and reperfusion injury (IRI) is one of the main barriers to graft survival. When tested in other transplanted organs, paclitaxel and methotrexate associated with cholesterol-rich nanoparticles (LDE) showed beneficial effects. Objective: To assess whether paclitaxel and methotrexate can attenuate IRI in a rat model of lung Tx. Methods: 32 rats (donor/recipient) were divided into 2 groups submitted to Tx: Control and Drug (n = 8 Tx each). The Sham group consisted of 5 intact animals. Twenty-four hours before surgery, donors and recipients were treated with drugs or LDE alone. After 12 hours of cold ischemia, the lungs were transplanted and reperfused for one hour. Ventilatory mechanics, blood gas analysis, blood count, biochemistry, histology and gene and protein expression of inflammatory, apoptotic and proliferative markers were analyzed. Results: The grafts had a higher rate of perivascular edema (Sham = 0.28 ± 0.23; Control = 2.09 ± 0.59; Drug = 2.17 ± 0.45; p = <0.001) and hemorrhage (Sham = 1.07 ± 0.03; Control = 1.77 ± 0.35; Drug = 1.76 ± 0.38; p = 0.005). TLR4 gene expression was lower in the Drug group (Control 1.32 ± 0.29; Drug 0.93 ± 0.12; p = 0.037). Conclusion: the tested drugs were not effective in attenuating the effects of ischemia and reperfusion injury.