This study was designed to evaluate the efficacy of combination treatment of pemetrexed plus oxaliplatin as second-line treatment in advanced/metastatic non-small cell lung cancer (NSCLC) patients who have failed first-line platinum-based chemotherapy, assuming that oxaliplatin can overcome the resistance to a platinum agent and translate into better outcome. Patients having shown progressive disease on first-line platinum-based chemotherapy received pemetrexed (500 mg/m(2)) and oxaliplatin (120 mg/m(2)) every 21 days till disease progression, unacceptable toxicity, or patient's refusal. As a result, 15 patients (10 squamous cell carcinoma, 15 men, and 12 ECOG of 1) participated in this study. Disappointedly, there was no response and 2 stable diseases, and therefore, as per protocol, we stopped the study early. Median survival time was 6.1 months. In conclusion, treatment with oxaliplatin and pemetrexed did not show activity in this population as second-line treatment. Further investigation could not be recommended or should be made in more selected population, such as, non-squamous NSCLC patients.