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Diffuse large B-cell lymphoma is the most common subtype of lymphoma. First-line treatment with combination chemoimmunotherapy is successful in about 60% of patients. For those who have relapse, second-line therapy consists of additional chemoimmunotherapy followed by autologous stem cell transplant. But most of these patients do not have good outcomes. The U.S. Food and Drug Administration (FDA) has approved CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) for third-line treatment; CAR-T is also effective for relapsed disease. The study described in this article examines whether CAR-T could be used as second-line therapy. Visual Abstract. Second-Line Chimeric Antigen Receptor T-Cell Therapy in Diffuse Large B-Cell Lymphoma: Diffuse large B-cell lymphoma is the most common subtype of lymphoma. First-line treatment with combination chemoimmunotherapy is successful in about 60% of patients. For those who relapse, second-line therapy consists of additional chemoimmunotherapy followed by autologous stem cell transplant. But most of these patients do not have good outcomes. The U.S. Food and Drug Administration (FDA) has approved CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) for third-line treatment; CAR-T is also effective for relapsed disease. The study described in this article examines whether CAR-T could be used as second-line therapy. Background: First-line treatment of diffuse large B-cell lymphoma (DLBCL) achieves durable remission in approximately 60% of patients. In relapsed or refractory disease, only about 20% achieve durable remission with salvage chemoimmunotherapy and consolidative autologous stem cell transplantation (ASCT). The ZUMA-7 (axicabtagene ciloleucel [axi-cel]) and TRANSFORM (lisocabtagene maraleucel [liso-cel]) trials demonstrated superior event-free survival (and, in ZUMA-7, overall survival) in primary-refractory or early-relapsed (high-risk) DLBCL with chimeric antigen receptor T-cell therapy (CAR-T) compared with salvage chemoimmunotherapy and consolidative ASCT; however, list prices for CAR-T exceed $400 000 per infusion. Objective: To determine the cost-effectiveness of second-line CAR-T versus salvage chemoimmunotherapy and consolidative ASCT. Design: State-transition microsimulation model. Data Sources: ZUMA-7, TRANSFORM, other trials, and observational data. Target Population: "High-risk" patients with DLBCL. Time Horizon: Lifetime. Perspective: Health care sector. Intervention: Axi-cel or liso-cel versus ASCT. Outcome Measures: Incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (iNMB) in 2022 U.S. dollars per quality-adjusted life-year (QALY) for a willingness-to-pay (WTP) threshold of $200 000 per QALY. Results of Base-Case Analysis: The increase in median overall survival was 4 months for axi-cel and 1 month for liso-cel. For axi-cel, the ICER was $684 225 per QALY and the iNMB was −$107 642. For liso-cel, the ICER was $1 171 909 per QALY and the iNMB was −$102 477. Results of Sensitivity Analysis: To be cost-effective with a WTP of $200 000, the cost of CAR-T would have to be reduced to $321 123 for axi-cel and $313 730 for liso-cel. Implementation in high-risk patients would increase U.S. health care spending by approximately $6.8 billion over a 5-year period. Limitation: Differences in preinfusion bridging therapies precluded cross-trial comparisons. Conclusion: Neither second-line axi-cel nor liso-cel was cost-effective at a WTP of $200 000 per QALY. Clinical outcomes improved incrementally, but costs of CAR-T must be lowered substantially to enable cost-effectiveness. Primary Funding Source: No research-specific funding. [ABSTRACT FROM AUTHOR]