The sequential administration of methotrexate (MTX) and 5-fluorouracil (5-FU) has been claimed to be synergistic. To investigate the potential synergism in non-small cell carcinoma of the lung (NSCCL), 16 patients were treated with a 2-hr infusion of MTX 200 mg/m2 followed after 2 hr by 5-FU 1g/m2. All patients had an Eastern Cooperative Oncology Group performance status of greater than 2 and had received no previous chemotherapy. No responses were seen. This study demonstrates that sequential MTX and 5-FU in this dosage and schedule is ineffective in NSCCL.