Objective To establish patient-derived tumor xenograft (PDX) models of lung cancer in nude mice, and test the changes of histomorphological architecture and the expression levels of p63, napsin A and TTF-1 in the primary lung cancer tissues and the tissues of third-generation (F3) PDX models. Methods Tissue pieces of surgical specimens from 12 lung cancer patients(8 squamous cell carcinomas and 4 adenocarcinomas)were taken and subcutaneously engrafted into nude mice to establish PDX models. Samples of the primary lung cancer tissues from patients and its PDX model in mice after the F3 generation were examined by pathology using HE staining. The changes of expression levels of p63, napsin A and TTF-1 were detected by immunohistochemistry. Results A total of 5 cases of the F3 PDX models were established successfully, including 4 cases of squamous cell carcinoma (SCC) and one case of adenocarcinoma (ADC). The tissue samples of the PDX model showed the same histological features of the primary tumor tissues. The p63 protein was positively expressed in 84.3% of the SCC tissues and 96% of the PDX models, showing a non-significant difference (P > 0.05), while negatively expressed in the ADC tissues. The positive rate of napsin A protein expression was 66% of the ADC tissues and 72.4% of the F3 PDX models, without a significant difference between them (P > 0.05). The expressing rate of TTF-1 protein was 91% of the ADC tissues and 85% of the F3 PDX models, without a significant difference (P > 0.05) as well. In addition, both napsin A and TTF-1 were negatively expressed in the SCC tissues. Conclusions The PDX models of lung cancers we have established retained some of the key features of the primary cancers, such as histological architecture, genomic signature, cellular heterogeneity and drug responsiveness, providing an effective resource for the research and development of personalized screening and evaluating of the drug efficacy in clinical trials and the identification of biomarkers for drug responsiveness.