Pemetrexed and gemcitabine are both active agents for the treatment of locally advanced or metastatic NSCLC. We tested a novel biweekly combination of pemetrexed and gemcitabine for tolerability and efficacy in 45 elderly and/or poor performance status patients (44% female, mean age of 72.4 years) with measurable stage IIIB/IV NSCLC. Patients received biweekly cycles of pemetrexed 500 mg/m(2) IV over 10 min followed by gemcitabine 1500 mg/m(2) IV with vitamin B12 1000 microg IM, and folic acid 1mg po daily beginning 7 days before and continuing throughout treatment (median of 4 cycles). Ten patients experienced grade 3/4 neutropenia, two had grade 3 febrile neutropenia, and two had grade 3 anemia. Patients with ECOG PS 2 appeared poorly suited for the regimen, with 61.5% completing < or = 2 cycles. The overall response rate was 17.8%, the clinical benefit rate (CR+PR+SD >24 weeks) was 26.7%, and the median progression free survival was 3.5 months. However, ECOG 0-1 patients had longer PFS and tended to have a better response rate than ECOG 2 patients.