Background: Non-small cell lung carcinomas represent the most common and the most aggressive entity of lung cancers, with a poor prognosis and decreased survival time. The clinical diagnosis is usually based on histopathology, immunohistochemistry and molecular analysis to describe the precise histological subtype and target therapies. Patients and Methods: Immunohistochemistry technical based on monoclonal antibodies of cytokeratin 5/6 and epidermal growth factor receptor was performed using the EnVision+ system on formalin-fixed paraffin-embedded samples for differential diagnosis of non-small cell lung carcinomas. Results: The imunostaining of epidermal growth factor receptor and cytokeratin 5/6 conducted on lung adenocarcinomas and squamous cell lung carcinomas sections shows a negative staining of the cytokeratins 5/6 in more than half of adenocarcinomas and an over-expression of the epidermal growth factor receptor in all cases. Only 37% of adenocarcinomas cases have provided a membrane and non-diffuse cytoplasmic immunostaining of cytokeratin 5/6. The patient having squamous carcinoma revealed an intense and diffuse positive staining of cytokeratin 5/6. Conclusion: Therefore, differential diagnosis using cytokeratins 5/6 must absolutely be supplemented with other specific markers.