OBJECTIVES: Lung cancer is the leading cause of cancer deaths worldwide (1.38 million cancer deaths, 18.2% of the total) and of cancer morbidity (1.61 million new cases, 12.7% of all new cancers). Currently only three second-line (2L) non-small cell lung cancer (NSCLC) pharmacotherapies are licensed in the European Union, the chemotherapies pemetrexed and docetaxel as well as the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) erlotinib. These therapy alternatives have shown a comparable efficacy (survival benefit). In the past cost comparisons showed that erlotinib was less costly compared to docetaxel, which itself was cheaper than pemetrexed. Nowadays erlotinib (and docetaxel) are still less expensive than pemetrexed; but docetaxel lost patent protection (basic compound patent) at the end of 2010, so the docetaxel drug costs have decreased rapidly, which poses the question of whether erlotinib still is the least costly therapy alternative in 2L NSCLC. METHODS: Italy has been selected exemplarily to compare the total therapy costs, estimated by combining country-specific drug costs, administration costs and adverse event costs of erlotinib and generic docetaxel in 2L NSCLC therapy. Sensitivity analyses on central input parameters have been performed. RESULTS: The total costs of treating one patient with erlotinib therapy of €5121 are lower than the docetaxel costs of €6699 for the Italian healthcare setting. Although the drug costs of erlotinib are higher than generic docetaxel (incremental €3770), the costs of intravenous chemotherapy administration (incremental -€4510) and the costs of adverse event therapy (incremental -€837) lead to higher total therapy costs of docetaxel compared to the EGFR TKI therapy erlotinib. CONCLUSIONS: The cost comparison findings for Italy show that erlotinib is still the less costly therapy alternative in 2L NSCLC. These results were robust to changes of central input parameters and robust to further potential price decreases for docetaxel.