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 10,329.85comparedtoaseriesoffiveTPEprocedures,whichhaddirectcostsof 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.