BACKGROUND The primary objectives of this study were to determine the efficacy and tolerability of a pemetrexed‐carboplatin combination as first‐line therapy in patients with advanced nonsmall cell lung cancer. METHODS Eligibility criteria included Zubrod performance status of 0 or 1, Stage IIIB (malignant effusion) or IV disease, and no prior chemotherapy. Treatment was pemetrexed 500 mg/m2 given intravenously and carboplatin area under the serum concentration–time curve = 6 given intravenously on Day 1 every 3 weeks for six cycles; patients could receive additional cycles at the discretion of the treating physician and patient. All patients received folic acid, vitamin B12, and dexamethasone prophylaxis. RESULTS Fifty patients (31 men and 19 women) were treated. The median age was 62 years. Ninety‐six percent of patients had Stage IV disease, and 88% had a performance status of 1. The median number of cycles was 6; 15 patients received 8 or more cycles. There was Grade 3/4 neutropenia in 11 (22%) and 2 (4%) patients, respectively; Grade 3/4 thrombocytopenia in 1 (2%) and 0 patients, respectively. Three patients (6%) experienced Grade 3 nonhematologic side effects (diarrhea, neutropenic pneumonia, and fatigue). No patients had sensory neuropathy or alopecia >Grade 1. The partial response rate was 24%, median time to progression 5.4 months, 1‐year survival 56.0%, and median survival 13.5 months. CONCLUSIONS This is an active, very well‐tolerated regimen. Trials focused on how to integrate this doublet with novel agents are warranted. Cancer 2005. © 2005 American Cancer Society. The primary objectives of this study were to determine the efficacy and tolerability of a pemetrexed‐carboplatin combination as first‐line therapy in patients with advanced nonsmall cell lung cancer.