Background: Tazemetostat, a first-in-class oral, selective methyltransferase inhibitor of enhancer of zeste homolog 2 (EZH2) activity, was approved by the US Food and Drug Administration for treatment of patients with R/R FL after demonstrating single-agent antitumor activity in patients with wild-type or mutant EZH2. Phosphoinositide 3-kinase inhibitors (PI3Kis; idelalisib, duvelisib, and copanlisib) are also indicated for 3L+ R/R FL, but these drugs are associated with serious toxicities, such as neutropenia, infection, and immune-mediated toxicities. A matching-adjusted indirect comparison (MAIC) of tazemetostat with these 3 PI3Kis was previously presented in 3L+ R/R FL, showing that tazemetostat is associated with more favorable safety, and similar efficacy compared to each of the PI3Kis. The objective of this study was to estimate the difference in AE-related health care costs for each treatment. Methods: AE-related costs were sourced from a study of costs in patients hospitalized with AEs, using oncology-specific data when available. Matching-adjusted AE incidence was multiplied by costs related to each AE. Grade ≥3 AEs with incidence ≥5% for any of the evaluated treatments were included. Cost differences were estimated per treatment episode, based on duration of exposure in the tazemetostat clinical trial (9.3 months for tazemetostat, <7 months for the 3 comparators). Incidence rates were then converted to a monthly basis using an exponential curve. Results: The PI3Kis are estimated to incur $13,534 to $18,737 higher AE-related management costs per episode compared with tazemetostat. Adjusting for duration of exposure, each of the PI3Kis is project to cost $2,563 to $3,820 more per month than tazemetostat in AE-related costs. These estimates indicate that the AE-related cost impact of PI3Kis compared with tazemetostat is 3.4- to 6.1-fold higher on a per-episode basis, and 5.0- to 10.4-fold higher on a monthly basis. Conclusions: Quantifying the AE cost impact of tazemetostat based on AE incidence rates estimated by MAIC analysis adjusts for population differences and allows for more direct cost savings comparisons when accounting for duration of exposure to different treatments. Patients with 3L+ R/R FL who are treated with tazemetostat are estimated to incur substantially lower AE-related costs compared with PI3Kis (idelalisib, duvelisib, and copanlisib).