Background: The most common frontline treatment for peripheral T-cell lymphoma (PTCL) is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or a CHOP-like regimen. In the recently reported phase 3 ECHELON-2 trial, brentuximab vedotin (BV) in combination with CHP (A+CHP) demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) compared to CHOP, with a manageable safety profile. The objective of this analysis was to evaluate the cost-effectiveness of A+CHP in the frontline setting for CD30-expressing PTCL. Methods: A partitioned survival model consisting of 3 health states (PFS, post progression survival, and death), was constructed using clinical and quality of life data from ECHELON-2 from a US payer perspective over a lifetime time horizon. PFS and OS observed from ECHELON-2 were extrapolated using standard parametric distributions. The best-fitting distributions (log-normal for both arms) were selected based on statistical goodness of fit and clinical plausibility of the long-term projections. Health utilities were derived from the European Quality of Life 5-Dimensions (EQ-5D) data collected in ECHELON-2. The average utility scores for the pre- and post-progression periods were estimated via a repeated-measures mixed-effects model. Medical resource use and costs were from literature. Results: The model predicted A+CHP extended undiscounted PFS by 2.92 and OS by 3.38 years over CHOP. These survival gains drive the value in the model. After adjusting for quality of life and discounting, A+CHP was associated with 1.79 quality-adjusted life years (QALYs) gained at an incremental cost of $176,842, yielding an incremental cost-effectiveness ratio (ICER) of $98,987. Sensitivity analyses of alternative model assumptions provided ICERs from $64,000 to $154,000. The estimated probability that A+CHP is cost-effective compared with CHOP was 75% at a willingness-to-pay threshold of $150,000. Conclusions: Based on the ECHELON-2 trial data, this analysis showed for patients with previously untreated CD30-expressing PTCL, treatment with BV in combination with CHP is likely to be cost-effective in comparison to CHOP.