Abstract: To investigate if the combination of erlotinib and cetuximab can overcome drug resistance in NSCLC with the T790M mutation and enhance the effects in NSCLC without somatic mutations in their epidermal growth factor receptors ( EGFR ). Methods: The effects of the combination of erlotinib and cetuximab in the primary NSCLC cells with the T790M and L858R mutations and without somatic mutations in their EGFR were investigated. Results: The effects of the combination of cetuximab and erlotinib on the growth of EGFR TKI-resistant primary NSCLC cells with T790M mutation and without EGFR mutation suspension in vitro were investigated. The combination had a more pronounced growth inhibition than the single-agent treatment in the primary NSCLC cells with T790M mutation ( P < 0.05 ), but not in the primary NSCLC cells without EGFR mutation. Conclusion: The current date data suggest that the combination of erlotinib and cetuximab is an effective strategy for the treatment of patients with EGFR TKI-resistant NSCLC and indicate combined EGFR targeting as a clinically exploitable strategy.