Background: Generally, tyrosine kinase inhibitor (TKI) therapy is recommended in first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) harbouring a classic epidermal growth factor receptor (EGFR) mutation. However, the response of patients with rare or complex EGFR mutations to TKI treatment is not predictable, nor is the prognosis for such patients. Objectives: In cases of rare or complex EGFR mutations, the right approach to therapy remains challenging. That is why we sought to analyse the characteristics as well as the prognosis and the response to TKI treatment of patients with rare or complex EGFR mutations. Patients and Methods: 343 NSCLC patients tested for EGFR mutation at a German lung cancer centre were analysed for age, gender, and smoking status as well as for the mutation status. For 12 patients with rare and complex mutations, response to TKI treatment was described. Results: 282 of all patients had a wild-type EGFR, whereas 61 harboured an EGFR mutation. 32 of these were classic mutations, followed by 16 rare and 7 complex mutations. EGFR mutations were significantly more frequent in women. Patients with rare or complex mutations were significantly more often smokers compared to those with classic EGFR mutations. Furthermore, rare and complex mutations were less responsive to TKI therapy. Conclusion: Patients with rare or complex EGFR mutations differ from those with classic mutations in terms of smoking status and response to TKIs. As these mutations may not respond well to TKI therapy, first-line TKIs should not be automatically chosen based on the sole presence of an EGFR mutation.