The activity of erlotinib after gefitinib failure in non-small cell lung cancer patients with all four favorable clinical factors including female, never smoker, Asian, and adenocarcinoma histology for tyrosine kinase inhibitors (TKIs) is not well known. Treatment efficacy of erlotinib (150mg daily) after progression on gefitinib (250mg daily) was analyzed in patients exhibiting the four clinically favorable factors. Sixteen consecutive female, never smoker, Korean (Asian), adenocarcinoma patients who received erlotinib after gefitinib failure were analyzed. The disease control rate for gefitinib was 68.8% (95% CI, 0.44-0.86) while the disease control rate for erlotinib following gefitinib failure was 25.0% (95% CI, 0.10-0.50) comprised of one partial response and three stable disease patients. The median progression free survival was 6.3 months for gefitinib treatment and 1.7 months for erlotinib treatment following gefitinib failure. The efficacy of erlotinib after progression on gefitinib is unsatisfactory in patients with four favorable clinical factors for TKIs. Novel treatment approaches such as the use of irreversible TKIs or anti-cMET agents for those patients are warranted.