Background: The recently reported ZUMA-7 and TRANSFORM trials demonstrate superior event-free survival among patients with primary refractory or early relapsed DLBCL compared to salvage chemotherapy with ASCT. However, given a cost of >$370,000, it is not known whether second-line CAR-T is cost-effective compared to ASCT. Thus, we developed a state-transition microsimulation model to simulate clinical outcomes and costs associated with therapy for DLBCL patients in first relapse, using ZUMA-7 and TRANSFORM data. Methods: The model begins at initiation of second-line therapy comparing salvage chemotherapy with ASCT or CAR-T therapy. We examined a three-year time horizon, including crossover to the alternative strategy therapy in the third line, as well as subsequent lines of therapy, using open-source Amua 0.3.0 software. Base case analysis was performed using 1000 first-order Monte Carlo simulations and probabilistic sensitivity analysis (PSA) was performed with 1000 simulations to test model uncertainty. Conditional probabilities of survival and disease progression were extracted from Kaplan-Meier curves from pivotal clinical trials using the WebPlotDigitizer tool. Costs were estimated from public sources in US Dollars ($) and effects were estimated in quality-adjusted life years (QALY) using published utility values. Results: Median overall survival was 15 months (95% confidence interval [CI] 13-19 months) with ASCT and 21 months (95% CI 17-29 months) with CAR-T. The PSA demonstrated costs and effectiveness per patient of $243,581 and 1.06 QALYs with ASCT and $470,150 and 1.22 QALYs with CAR-T with an incremental cost-effectiveness ratio (ICER) of $1,383,320/QALY. Incremental net monetary benefit of CAR-T versus ASCT, based on a willingness-to-pay (WTP) threshold of $200,000/QALY, was -$193,812. The break-even price for CAR-T and all subsequent therapies, based on a one-way sensitivity analysis, was $170,489. Conclusions: The model demonstrated improved survival and QALYs for the second-line CAR-T therapy, but was not cost-effective, as the ICER exceeded $1,000,000/QALY, which is higher than most accepted WTP thresholds. A limitation of these early data is that they only assess outcomes over three years. To estimate the full effect of these therapies, we will extrapolate the Kaplan-Meier curves for additional analyses. Clinical outcomes of second-line CAR-T are promising, but prices would need to be considerably lower to enable equitable access and affordability.