Oral gefitinib tablets are widely clinically applied for the treatment of non-small cell lung cancer (NSCLC) though its broad distribution in the body may result in weak therapeutic efficiency and unexpected side effects. Here, liposomal gefitinib dry powder inhalers (LGDs) were prepared using the injection-lyophilization method. LGDs were rough porous particles under the scanning electron microscope, which can be rapidly rehydrated to liposomes. LGDs and gefitinib powders were separately intratracheally (i.t.) administered into the lungs of primary lung cancer rats, while powdered gefitinib tablets were orally administered. Gefitinib was rapidly absorbed from the lung after i.t. administration of LGDs. The maximal gefitinib concentration in the circulation and the area under curve (AUC) of i.t. LGDs were higher than those of i.t. gefitinib powders and oral gefitinib. More importantly, much higher concentration and longer retention of gefitinib in the lung were shown after i.t. administration of LGDs and gefitinib powders but remarkably less drug distribution in the liver compared to oral gefitinib. LGDs showed higher therapeutic effect on primary lung cancer than i.t. gefitinib powders and oral gefitinib with reduction of inflammation, weak lung injury, and high apoptosis. Combination of inhalation and liposomes of anticancer drugs is a promising strategy for treatment of primary lung cancer.Copyright © 2020. Published by Elsevier B.V.