OBJECTIVES: To elucidate the more cost-effective dosing strategy for the administration of pemetrexed in the second-line treatment of patients having been treated for advanced non-small cell lung cancer (NSCLC). METHODS: Validation of the model was based on efficacy and safety data from a phase II clinical study conducted in Japan of two pemetrexed doses: 500 mg/m2 (P500) vs. 1000 mg/m2 (P1000).  Cost-effectiveness and cost-minimization analyses were performed to estimate the impact of P500 versus P1000 on expected life years and costs from the perspective of the Japanese national health insurance (NHI) system.  Costs covered additional treatment and test which are needed due to the treatment of pemetrexed and adverse events.  A sub-group analysis was conducted to compare the cost-effectiveness of pemetrexed in patients with different NSCLC histologies. RESULTS: P1000 exhibited a negative life years gained (LYG) of - 0.115 at an incremental cost of US$13,674 compared to P500, implying simple dominance of P500 over P1000.  The incremental cost-effectiveness ratio (ICER) of pemetrexed therapy with P500 was estimated at US$19,479/LYG, compared with the same therapy in squamous cell carcinoma, when it is performed in non-squamous cell carcinoma.  Results of a probabilistic sensitivity analysis demonstrated an almost 100% likelihood of the ICER of pemetrexed with P500 for non-squamous cell patients falling below the threshold of US$50,000/LYG. CONCLUSIONS: P500 is a more cost-effective dosing regimen than P1000 for pemetrexed chemotherapy in patients with NSCLC. Also, results suggest that pemetrexed is more cost-effective in NSCLC patients of non-squamous histology than of squamous histology from the payer’s perspective.