OBJECTIVES: To assess the cost-effectiveness of pemetrexed/cisplatin vs. gemcitabine/cisplatin in the first-line treatment of advanced or metastatic non-small cell lung cancer (NSCLC) patients with an adenocarcinoma tumour histology. METHODS: A Markov model developed to estimate the costs and benefits of pemetrexed/cisplatin vs. gemcitabine/cisplatin in the first-line treatment of NSCLC patients was populated with Italian unit cost data.  As the incidence and prevalence of adenocarcinoma is higher than any other type of non-squamous NSCLC in Italy, the model focuses on patients with adenocarcinoma histology. The model consists of health states for stable disease, response, progressive disease and death. Patients receiving chemotherapy could also experience adverse events within the stable and response states. The clinical inputs (response rates, overall survival, progression-free survival and adverse event rates) were obtained from a phase III randomised trial comparing pemetrexed/cisplatin and gemcitabine/cisplatin. The analysis was from the Italian health care system perspective, with a 3–year horizon. Outcomes included direct medical costs (chemotherapy; adverse events; best supportive care; terminal/palliative care), life years gained (LYG) and quality-adjusted life years (QALYs), all discounted at a rate of 3%.   RESULTS: Total LYG was 1.26 for patients treated with pemetrexed/cisplatin and 1.15 for patients treated with gemcitabine/cisplatin. Total QALYs were 0.67 for the pemetrexed arm compared to 0.62 for the gemcitabine arm. The total cost per patient was €20,438 for pemetrexed/cisplatin and €17,605 for gemcitabine/cisplatin. These model outputs result in incremental cost-effectiveness ratios of €24,507 per LYG, and €48,666 per QALY gained. Univariate sensitivity analyses show that the results are most sensitive to overall survival. CONCLUSIONS: For oncolytics in Italy, €70,000/QALY is often considered a good indication of willingness-to-pay threshold. According to the model, pemetrexed/cisplatin is a cost-effective alternative to gemcitabine/cisplatin in the first-line treatment of NSCLC patients within the adenocarcinoma population.