OBJECTIVES: First- and second-line treatment costs range from $140,000 to $200,000. A model was developed to estimate lifetime direct medical costs of third-line and subsequent treatment costs for relapse/refractory diffuse large B-cell lymphoma (RR DLBCL) in the United States. METHODS: A disease cost model using partitioned survival analysis and adopting a provider perspective was developed. Third-line therapy is a weighted average of recommended regimens, including chemotherapy and stem cell transplantation (SCT). Costs of therapies are based on Average Sales Price (ASP) and direct costs to providers in $2017. Costs include adverse events, treatment administration and monitoring, disease management, and future healthcare costs. Patients who achieve a complete or partial response do not proceed to subsequent therapy; patients who are in stable disease / progressive disease receive one line of subsequent therapy. Patients who fail third-line therapy or who cannot proceed with the intended therapy are transitioned to palliative care. Sensitivity analyses examine variation in therapy efficacy and chemotherapy regimen and SCT weighting. RESULTS: Lifetime costs, including third-line and subsequent therapy, ranges from $600,000 to $750,000. The costs of adverse events related to the third-line treatment represent the largest proportion (about 30%) of the total cost. Treatment acquisition of the third-line therapy (28%) and subsequent therapy (21%) are other leading cost drivers. CONCLUSIONS: The costs of current therapies for the treatment of RR DLBCL can be very high. Including first- and second-line therapy, total lifetime cost can approach at least $1 million. More effective novel therapies can moderate lifetime costs by ensuring durable remission, which may offset the proportion of patients who proceed to subsequent treatment. Economic evaluations of novel therapies should consider long-term outcomes as they are major contributors to lifetime costs. Further research on real-world lifetime costs and outcomes are needed to inform future treatment decision models.