11105 Background: Four liso-cel clinical trials in R/R LBCL (TRANSCEND NHL 001, PILOT, OUTREACH, and TRANSFORM) demonstrated a favorable clinical profile with high response rates (73%–80%) and positive changes in HRQoL after treatment. This analysis pooled data across 4 trials to assess the impact of clinical response and AEs on HRQoL. Methods: The EORTC QLQ-C30 and EQ-5D-5L were used to assess HRQoL repeatedly at prespecified time points up to Day 730. Six clinically relevant domains (EORTC QLQ-C30 global health status/quality of life [GHS/QoL], physical functioning, cognitive functioning, fatigue, pain, and the EQ-5D-5L visual analog scale [VAS]) were analyzed in liso-cel–treated pts pooled across trials with HRQoL scores at baseline and postbaseline visits. Linear mixed-effects regression models examined changes in HRQoL over time, with clinical response status and AEs as time-varying covariates, adjusting for relevant baseline and other time-varying factors. Trends in HRQoL change up to Day 730 over time were examined by cytokine release syndrome (CRS) and neurological events (NE) occurring ≤ 30 days after infusion. Results: The analysis included 368 and 372 pts for EORTC QLQ-C30 and EQ-5D-5L VAS, respectively. Achieving a clinical response (CR or PR) was associated with significant HRQoL improvement versus stable disease (SD) or PD in all 6 domains (Table). Meaningful improvement occurred ≤ 30 days after achieving CR or PR for all domains except cognitive functioning, where improvement occurred ≤ 90 days, and was sustained across remaining follow-up visits. CRS and NEs were associated with HRQoL worsening in selected domains; however, pts who experienced CRS or NEs ≤ 30 days after infusion recovered to levels of pts without the AE by Day 60 and maintained thereafter. Conclusions: Among liso-cel–treated pts with R/R LBCL, positive clinical response was associated with meaningful and sustained improvement in nearly all HRQoL domains. CRS and NEs may negatively impact certain HRQoL domains but are temporary. As liso-cel has demonstrated high response rates and a manageable safety profile across studies, these findings further support the pt-reported benefits of liso-cel for R/R LBCL. [Table: see text]