BACKGROUND: Controlled trials have found therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIg) infusion therapy to be equally efficacious in treating Guillain-Barré syndrome (GBS). Due to increases in the price of IVIg compared to human serum albumin (HSA), used as a replacement fluid in TPE, we examined direct hospital-level expenditures for TPE and IVIg for meaningful cost-differences between these treatments. METHODS: Using financial data from our two institutions, hospital cost profiles for IVIg and 5% albumin were established. Reimbursement amounts were obtained from publicly available Medicare data resources to determine payment rates for TPE, non-tunneled central catheter line placement, and drug infusion therapy. A model was developed which allows hospitals to input cost and reimbursement amounts for both IVIg and TPE with HSA that results in real-time valuations of these interventions. RESULTS: The direct cost of five IVIg infusion sessions totaling 2.0 grams per kilogram (g/kg) body weight was $10,329.85 compared to a series of five TPE procedures, which had direct costs of $4,638.16. CONCLUSIONS: In GBS patients, direct costs of IVIg therapy are more than twice that of TPE. Given equivalent efficacy and similar severity and frequencies of adverse events, TPE appears to be a less expensive first-line therapy option for treatment of patients with GBS.