OBJECTIVES: Clinicians treating patients with advanced NSCLC have a range of options for care. The objective of this study was to develop a cost-effectiveness (CE) model to compare induction-maintenance sequences approved for use in the U.S. for the treatment of advanced non-squamous NSCLC given the absence of direct head-to-head trials. METHODS: The modelled regimens that were licensed in the United States included pemetrexed+cisplatin followed by (→) pemetrexed; pemetrexed+cisplatin→best supportive care (BSC); gemcitabine+cisplatin→BSC; gemcitabine+cisplatin→erlotinib; gemcitabine+cisplatin→pemetrexed; and paclitaxel+carboplatin+bevacizumab→bevacizumab. Treatment effects of induction and maintenance on survival endpoints were obtained using data from a previous network meta-analysis. Decision analytic modelling was used to synthesise the treatment effect and baseline risk estimates for the induction and maintenance treatment sequences. The CE model was structured using an area-under-the-curve approach, costs and benefits were discounted at 3.5% per annum, and probabilistic and one-way sensitivity analyses were conducted to evaluate model parameters. RESULTS: All active maintenance therapy-containing regimens, with the exception of gemcitabine+cisplatin→erlotinib, were more costly than induction-only regimens. Gemcitabine+cisplatin→BSC was the baseline comparator and established the cost effective threshold range of $0 to $121,425. The respective incremental costs per life year (LY) were $121,425, $148,994, and $191,270 for gemcitabine+cisplatin→erlotinib versus gemcitabine+cisplatin→BSC, pemetrexed+cisplatin→BSC versus gemcitabine+cisplatin→erlotinib, and pemetrexed+cisplatin→pemetrexed versus pemetrexed+cisplatin→BSC. Other regimens were dominated (paclitaxel+carboplatin+bevacizumab→bevacizumab) or extendedly dominated (gemcitabine+cisplatin→pemetrexed). Sensitivity analyses demonstrated that efficacy data and the method of extrapolating survival had the greatest impact on the cost-effectiveness results. For non-dominated regimens, the cost-effectiveness acceptability frontier showed that gemcitabine+cisplatin→BSC, pemetrexed+cisplatin→BSC, and pemetrexed+cisplatin→pemetrexed had the greatest probabilities of cost-effectiveness over the following threshold ranges: $0-$124,000/LY; $124,000-$220,000/LY; and above $220,000/LY, respectively. CONCLUSIONS: Depending on the specific cost-effectiveness threshold used by a decision maker, the cost-effective treatment sequence will be gemcitabine+cisplatin→BSC, gemcitabine+cisplatin→erlotinib, pemetrexed+cisplatin→BSC, or pemetrexed+cisplatin→pemetrexed. Paclitaxel+carboplatin+bevacizumab→bevacizumab and gemcitabine+cisplatin→pemetrexed were dominated or extendedly dominated and thus not cost-effective when ranking these comparators.