(1) Introduction: BEAM is a high-dose chemotherapy (HDCT) frequently administered before autologous stem cell transplantation (ASCT) in diffuse large B-cell lymphoma (DLBCL). Bendamustine replacing BCNU (BeEAM) is similarly effective at lower toxicities. However, relapse remains the major cause of death in DLBCL. (2) Methods: This is a 12-patient pilot study of the BeEAM preparative regimen with additional polatuzumab vedotin (PV, targeting CD79b) aiming to establish feasibility and to reduce toxicity without increasing the early progression rate. PV was given once at the standard dose of 1.8 mg/kg at day −6 together with BeEAM-HDCT (days −7 to −1) before ASCT. (3) Results: 8/12 patients (67%) received PV with BeEAM as a consolidation of first-line treatment, and 4/12 patients (33%) received PV with BeEAM after relapse treatment. All patients experienced complete engraftment (neutrophils: median 11 days; platelets: 13 days). Gastrointestinal toxicities occurred in 7/12 patients (58%, grade 3). All patients developed neutropenic infections with at least one identified pathogen (bacterial: 10/12 patients; viral: 2/12; and fungal: 1/12). The complete remission rate by PET-CT 100 days post-ASCT was 92%, with one mortality due to early progression. Eleven out of twelve patients (92%) were alive without progression after a median follow-up of 15 months. (4) Conclusions: Our study with 12 patients suggests that combining PV with BeEAM HDCT is feasible and safe, but the limited cohort prevents definite conclusions regarding efficacy. Larger cohorts must be evaluated.