OBJECTIVES: The purpose of this study was to compare the costs of the drug, drug administration and managing of adverse events (AEs) using erlotinib, docetaxel and pemetrexed as second line therapy in non-small cell lung cancer (NSCLC), in the Italian hospital setting. METHODS: Since a clinical study comparing the three therapies is not available, the major clinical findings from randomized trials of each drug were used showing that all three chemotherapies have comparable efficacy results. Therefore a cost-minimization analysis was performed. Costs from the hospital perspective were calculated according to Italian clinical practice. Consumption of each chemotherapy was based on respective clinical trial, while to estimate the resources used in the AEs and for the drug administration a Delphi panel of experts was structured. In order to allow a comparison between an oral daily therapy (erlotinib) and infusion therapies administered every 21 days (docetaxel and pemetrexed), costs were computed on a monthly base. RESULTS: The total per-patient cost for erlotinib was €1669, €2569 for docetaxel and €3324 for pemetrexed for one month therapy from the hospital perspective. The cost of AEs represents the 8%, 18%, and 3% of the total cost for erlotinib, docetaxel and pemetrexed. Sensitivity analysis showed that no reasonable changes in the quantity and cost of services reduced the savings associated with erlotinib by more than 33%. CONCLUSION: A cost-minimization analysis was performed to assess the cost of three second line chemotherapies in non-small cell lung cancer. The less costly alternative was erlotinib which could produce savings between 40% an 50% of total hospital costs in Italy.