Background: The BCL-2 inhibitor venetoclax (Ven) has shown activity in MM with t(11;14). However, a randomized trial comparing bortezomib and dexamethasone ± Ven in unselected MM patients was notable for decreased overall survival (OS) in the non-t(11;14) population treated with Ven despite improved progression free survival (PFS). In a subgroup analysis of 35 t(11;14) patients, those randomized to the Ven arm had superior OS (HR, 0.61 [95% CI, 0.16-2.32]) but this did not reach statistical significance (Kumar et al, Blood 2021). We sought to investigate the real-world impact of Ven-based therapy in t(11;14) MM and to explore patient and disease-related factors impacting response and durability. Methods: We retrospectively identified all t(11;14) MM patients treated at Moffitt Cancer Center between 2000-2022. The primary endpoint was OS measured from the time of MM diagnosis compared between Ven-treated patients and those who did not receive Ven. Secondary endpoints were ≥VGPR rate, PFS, and key toxicities. The era of MM diagnosis (5-year intervals) was included in analyses to account for novel therapies. Kaplan-Meier estimates and Cox regression were employed. Results: 262 MM patients were included. Median age was 64 years (interquartile range [IQR], 56-71 years); 61% were male; 87% were White. Ven was used in 78 patients (30%) on median in the 5^th line (IQR, 4-7) and most commonly in combination with anti-CD38 antibodies (42%) or proteasome inhibitor (32%). Most patients (77%) initiated treatment at 400 mg daily and 25% required dose reduction. At a median follow-up of 52 months, 18 (23%) patients died in the Ven group as compared to 87 (47%) in the non-Ven group. Median unadjusted OS was longer in the Ven group (206 months [95% CI, 112-249 months] vs 75 months [95% CI, 65-97 months]; p < 0.01). In multivariable analysis accounting for demographics, high-risk cytogenetics, time of diagnosis, penta-exposed status, autologous stem cell transplant and BCMA-directed therapy, Ven was associated with a reduced risk of death (HR, 0.26; 95% CI, 0.15-0.47). Of 73/78 with available response data, 38% achieved ≥VGPR with Ven-based therapy. Median PFS was 27 months (95% CI, 13-39 months). In univariable analyses, 1q amplification/gain was associated with inferior PFS (13 months [95% CI, 6.5-28 months]) vs 33 months [95% CI, 23 months-not reached/NR]; p = 0.04). Median PFS was longer anti-CD38 antibody (33 months [95% CI, 13 months-NR]) compared to proteasome inhibitor combinations (11 months [95% CI, 7 months-NR]), but this difference was not statistically significant (p = 0.1). No grade 3/4 infections or deaths were directly attributable to Ven. Conclusions: In this real world dataset, MM patients with t(11;14) treated with Ven-based combinations exhibited superior survival. The response to Ven may be impacted by the partner agent and concurrent cytogenetic abnormalities.