Emerging data suggest pemetrexed is active in patients with adenocarcinoma of lung compared to those with squamous cell carcinoma. We retrospectively reviewed advanced non small cell lung cancer (NSCLC) patients previously treated, analysing efficacy on histologic characteristics. From January 2007 to December 2010, 25 patients with stage IIIB or IV NSCLC (17 with adenocarcinoma and 8 with squamous cell carcinoma), who had previously failed on platinum-based chemotherapy, received pemetrexed 500 mg/mq every 3 weeks until disease progression or unacceptable toxicities. Analysing the histologic subgroups we observed 1 (5.9%) complete response, partial response in 5 patients (29.4%), stable disease in 6 (35.3%), progression disease in 5 (29.4%) in adenocarcinoma group compared to 4 (50%) stable disease and 4 (50%) progression disease in squamous cell carcinoma group. Median progression free survival was 8 months (range 3-22) for adenocarcinoma patients and 4 months (range 2-6) for squamous cell patients. According to data of the literature, also our small retrospective study conducted on unselected patients confirms the difference of pemetrexed efficacy by histology type, with better results in patients with adenocarcinoma lung cancer.