Objective: Evidence concerning the relationship between medical-care costs and tumor histology among advanced-staged NSCLC patients is lacking. The purpose of this analysis was to identify costs associated with first-line chemotherapy treatment and total lifetime medical-care costs by tumor histology among elderly Stage IIIB/IV NSCLC patients treated with commonly used doublet chemotherapy regimens. Methods: Study patients included those aged 65 years and older who were diagnosed with Stage IIIB/IV NSCLC in a SEER cancer registry between 1997 and 2002 and who received first-line treatment with a commonly used doublet regimen. Study patients were followed in the SEER-Medicare database to evaluate costs while on first-line chemotherapy treatment as well as lifetime medical-care costs by histology for commonly used doublets. Pairwise comparisons of costs estimated using non-parametric bootstrap methodology were generated for treatment comparisons. Estimated differences in mean costs, adjusted for sex, race age, urban/rural, geographic region, stage, Charlson comorbidity index and tumor histology are presented. Results: Total lifetime medical-care costs for elderly IIIB/IV patients with squamous cell carcinoma were $51,360, while costs for those with non-squamous cell carcinoma were $50,905. Costs per month were $6364 and $6870 respectively, and were dominated by hospital and physician utilization. Among commonly used doublets, the estimated difference in adjusted mean total costs for Cisplatin/Carboplatin (P) and a Taxane (T) were significantly higher when compared to P and Gemcitabine (G) (difference $4816 [$1554-$8101]). Similar findings were observed for costs while on first-line therapy, (difference $5686 [3738-$7630] respectively). Conclusion: While lifetime medical-care costs and costs while on first-line chemotherapy among treated Stage IIIB/IV NSCLC patients are substantial, the cost differential between squamous cell and non-squamous cell carcinoma is small. Controlling for tumor histology and other factors, patients treated with a combined platinum and taxane regimen experience the highest costs.