AbstractFludarabine/cyclophosphamide (Flu/Cy) is established for lymphodepletion (LD) prior to standard‐of‐care CAR T‐cell therapy for lymphoma. There is ongoing need to test alternative LD regimens to preserve efficacy, improve safety, and address challenges including the recent national fludarabine shortage. We retrospectively evaluated outcomes among patients with relapsed/refractory aggressive B‐cell lymphoma who received bendamustine (n = 27) or Flu/Cy (n = 42) LD before axicabtagene ciloleucel (axi‐cel) at our institution. The median change in absolute lymphocyte count from pre‐LD to time of axi‐cel infusion was −0.6×10⁹/L in bendamustine cohort and −0.7×10⁹/L in Flu/Cy cohort. The best overall response/complete response rates were 77.8% (95% CI: 57.7%–91.4%)/48.1% (95% CI: 28.7%–68.1%) among bendamustine cohort and 81.0% (95% CI: 65.9%–91.4%)/50.0% (95% CI: 34.2%–65.8%) among Flu/Cy cohort. Six‐month progression‐free survival were 43.8% (95% CI: 24.7%–61.3%) and 55.6% (95% CI: 39.0%–69.3%) in bendamustine and Flu/Cy cohorts, while 6‐month overall survival were 81.5% (95% CI: 61.1%–91.8%) and 90.4% (95% CI: 76.4%–96.3%), respectively. Relative to Flu/Cy‐treated patients, bendamustine‐treated patients did not show an increase in hazards associated with experiencing progression/relapse/death (aHR:1.4 [95% CI: 0.7–2.8]; p = .32) or death (aHR:1.6 [95% CI: 0.5–5.6]; p = .46), after adjusting for baseline number of prior therapies and refractory disease. Any grade/grade ≥3 CRS were observed in 89%/3.7% and 86%/4.8% among bendamustine and Flu/Cy cohorts, while any grade ICANS/grade ≥3 ICANS were observed in 30%/19% and 55%/31% respectively. While more Flu/Cy‐treated patients experienced grade ≥3 neutropenia compared with bendamustine‐treated patients (100% vs. 68%), grade ≥3 infectious complications were comparable (24% vs. 19% respectively). More patients received bendamustine LD and axi‐cel as outpatient than Flu/Cy cohort, without increased toxicities and with shorter median inpatient stays. In conclusion, we observed comparable efficacy and lower any grade ICANS among patients receiving bendamustine relative to Flu/Cy LD, followed by axi‐cel.