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Abstract: Adenosquamous carcinoma (ADSQ) is uncommon in non-small cell lung cancer (NSCLC). The frequency rate of ADSQ was 9.7% of 6990 primary lung cancers resected in our department. Many researches have analyzed genetic and molecular alterations in adenocarcinoma (AD) and squamous cell carcinoma (SQ), but few molecular studies have been conducted on heterogeneous ADSQ. The current study was to investigate gene mutations of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene (KRAS) and their correlation with clinical variables in Chinese patients with ADSQ. Histologic features were reviewed, and immunohistochemical (IHC) and molecular (EGFR and KRAS) studies were done in 55 Chinese patients with ADSQ. Microscopically, all the tumors demonstrated dual differentiation with varying proportions of AD and SQ. Based on morphological diagnosis, a combination of multiple IHC markers is helpful for accurately discriminating two undifferentiated histologic subtypes of ADSQ. EGFR mutations were identified in 21 (38.2%) patients: 11 mutations were in exon 19, 1 in exon 20, 7 in exon 21 and double mutations were found in two patients. We also found two new mutations, namely, L747-E749del K754A within exon 19 and H850R within exon 21. Moreover, 16 (29.1%) silent mutations Q787Q in exon 20 were found in the series, five of which coexisted with other mutations. EGFR mutations were more frequently found in patients with size of the tumors ≥3cm [19/35 (54.3%); 2/20 (10%); P =0.001] or coexistent double cancer. However, the EGFR mutation was not associated with gender, age, lymph node status, tumor stage and smoking history. KRAS mutations were present in 2 (3.64%) male patients in codon12 (G12C) and none of them showed EGFR mutation. Moreover, identical EGFR and KRAS mutations in both components of ADSQ were further confirmed by microdissection techniques. The data indicated that the incidence of EGFR and KRAS mutations in Chinese patients with ADSQ were similar to those of Asian patients with AD. Furthermore, EGFR silent mutations accounted for a large proportion in ADSQ. Additional prospective studies are needed in order to define the clinical relevance of new and silent mutation variants. [Copyright &y& Elsevier]