OBJECTIVES: Over the past decades, research focusing on new chemotherapeutic agents for patients with inoperable NSCLC have reported only modest gains in survival. These health gains are achieved at considerable costs, but economic evidence on superiority of one of the agents in terms of cost-effectiveness is lacking. The objective of this systematic review is to assess fully published cost-effectiveness studies comparing the new agents docetaxel, paclitaxel, vinorelbine, gemcitabine and pemetrexed, and the targeted therapies erlotinib and gefitinib among each other.  METHODS: PubMed, EMBASE.com and Economic Evaluations (via the Cochrane Library, Wiley) were systematically searched for fully published studies from the past 10 years. Studies were screened by two independent reviewers according to a priori inclusion criteria. The methodological quality of the included studies was evaluated by two independent reviewers using standardized assessment tools. RESULTS: A total of 222 potential studies were identified. Eleven cost-effectiveness or cost-utility studies were included. The methodological quality of the full economic evaluations was fairly good. Transparency in costs and resource use, details on statistical tests and sensitivity analysis were points for improvement. In first-line treatment, one study indicated that gemcitabine-cisplatin was cost-effective compared to paclitaxel-based regimens, and another study indicated that gemcitabine-cisplatin was cost-effective compared to platinum-based regimens containing either paclitaxel, vinorelbine or docetaxel in terms of progression-free survival. In a third study, pemetrexed-cisplatin was cost-effective compared to gemcitabine-cisplatin in patients with nonsquamous cell carcinoma. In second-line treatment, docetaxel was cost-effective compared to BSC (range of  ICERs per LYG: US$22,190-US$32,133). Erlotinib was cost-effective compared to placebo in one study (ICER per LYG: US$33,728). Docetaxel and pemetrexed were dominated by erlotinib in one study and in two studies, respectively. CONCLUSIONS: We found indications for superiority in terms of cost-effectiveness of gemcitabine-cisplatin in a first-line setting and for erlotinib in second-line setting.