OBJECTIVES Pemetrexed plus cisplatin (Cis/Pem) was recently approved in the US as initial treatment for advanced nonsquamous NSCLC. We developed a budget impact model to estimate the effect on a US health plan budget of adopting Cis/Pem for this new indication. METHODS A deterministic Excel-based budget impact model was developed from the perspective of a one million member US health plan over a one-year time horizon. A survey of nine US thoracic oncologists was used to quantify the impact of introducing Cis/Pem as first-line therapy on the frequency of chemotherapy use and the choice of first- and second-line regimens. Results were calculated from SEER incidence rates and the anticipated changes in first- and second-line regimen utilization rates. The costs associated with each regimen were based on Medicare reimbursement rates and a claims database analysis. Model outputs included health plan total cost, cost per patient per year, and per member per month (PMPM) costs. RESULTS Following the adoption of Cis/Pem, total cost per patient per year for advanced NSCLC is estimated to decrease by $702 from $67,539 to $66,837. Anticipating that the number of NSCLC patients receiving treatment over the course of one year would increase slightly, a net additional cost to the health plan of $35,512 is estimated. Overall a neutral PMPM cost ($0.00) is expected. Most sensitivity analyses produce PMPM costs between -$0.02 and $0.02. CONCLUSIONS Introduction of Cis/Pem as first-line therapy is anticipated to reduce the use of less expensive doublet regimens including gemcitabine and paclitaxel; however, it is also anticipated to reduce the use of more expensive triplet regimens containing bevacizumab. When Cis/Pem is used as first-line therapy, alternative, and often less expensive, regimens are recommended for use as second-line therapy. Overall, the adoption of Cis/Pem as first-line therapy for advanced nonsquamous NSCLC is anticipated to be budget neutral.