The purpose was to determine the optimal multifractionated (MF) dosing schedule to permit the delivery of four active agents in nonsmall cell lung cancer simultaneously in alternating doublets (docetaxel-cisplatin alternating with gemcitabine-vinorelbine). Three MF schedules were used: schedule A weekly; schedule B twice weekly for 2 weeks repeated every 21 days; and schedule C twice weekly every other week. Dose fractions were fixed for each component drug: docetaxel 50 mg/m2 plus cisplatin 20 mg/m2 and gemcitabine 500 mg/m2 plus vinorelbine 25 mg/m2. GCSF 480 micrograms was administered as a single dose concomitant with chemotherapy if the WBC was between 1500 and 3500 cells/mm3. Hematological toxicity, particularly leukopenia and anemia, was the predominant adverse effect observed and was demonstrated on all three schedules. Schedule B was not feasible in that none of the seven cycles were completed and six of seven required hospitalization for febrile neutropenia. The delivery of a four-drug combination chemotherapy regimen consisting of docetaxel, cisplatin, gemcitabine, and vinorelbine is feasible with an alternating doublet multifractionated dosing scheme with either a weekly or twice weekly every other week schedule.