OBJECTIVES: Diffuse large B cell lymphoma (DLBCL) is comprised of germinal center B cell-like (GCB) and activated B cell-like (ABC) subtypes; the latter is associated with worse survival with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) therapy. Preliminary evidence suggests that novel agents can improve ABC DLBCL survival when added to RCHOP, which motivates the implementation of precision medicine treatment strategies stratified by subtype. Our objective was to project the cost-effectiveness of subtype-based treatment strategies from a US payers’ perspective. METHODS: We developed micro-simulation models to compare three first-line treatment strategies for DLBCL: (1) standard treatment with RCHOP; (2) lenalidomide+RCHOP (R2CHOP); and (3) subtype-based treatment with subtype testing using immunohistochemistry (IHC) algorithms followed by RCHOP for GCB and R2CHOP for ABC (or non-GCB) DLBCL. Relapsed patients received salvage chemotherapy followed by autologous stem cell transplant as the current standard of care. Subtype-specific survival data were drawn from published clinical studies, and drug and administration costs were based on average wholesale price and Medicare physician fee schedule. We performed one-way and probabilistic sensitivity analyses to assess model robustness. RESULTS: RCHOP on average provided 6.2 QALYs (8.1 LYs) at a cost of $65,700; and subtype-based treatment improved health outcomes by providing 7.9 QALYs (10.2 LYs) at a cost of $86,400, leading to an incremental cost-effectiveness ratio of $12,500/QALY ($9,600/LY). R2CHOP provided 7.8 QALYs (10.5 LYs) at the highest cost of $123,300, which is dominated by subtype-based treatment. Sensitivity analyses demonstrated that our findings were robust with variations in model parameters. CONCLUSIONS: We demonstrated that subtype-based treatment has the potential to be cost-effective across variations in survival benefit and additional cost for the novel treatment. Data from randomized trials are needed to validate the cost-effectiveness profile and to guide the optimal use of standard and novel therapies for DLBCL in clinical practice.