Bispecific antibodies (BsAbs) have transformed the treatment landscape for DLBCL and FL, though approval for CLL has yet to be achieved. In this trial, patients with relapsed/refractory (R/R) CLL/SLL who had received ≥2 prior systemic therapies were treated with subcutaneous epcoritamab 48 mg in 28-day cycles. CRS mitigation strategies included adequate hydration and dexamethasone 15 mg prophylaxis. Similar to mantle cell lymphoma (MCL), CRS rates were higher in CLL than in DLBCL and FL. With mitigation, almost all CRS events were grade 1—fever alone—and 12% of patients experienced hypotension not requiring pressors. In the expansion cohort (EXP), the overall response rate (ORR) was 61%, with a complete response (CR) rate of 39%, and 75% of evaluable patients achieved undetectable minimal residual disease (uMRD) at the 10⁻⁴ threshold. Median progression-free survival was 12.8 months, and 65% of patients were alive at 15 months, with median overall survival not reached. Optimizing CRS mitigation strategies for CLL remains necessary, but these results highlight epcoritamab's potential as a promising treatment for high-risk R/R CLL.