Background/Objectives: CAR-T-cell therapy has become a key treatment for relapsed or refractory hematologic malignancies such as diffuse large B-cell lymphoma (r/r DLBCL), although patient outcomes differ considerably. The intestinal microbiome has been proposed as an important factor influencing CAR-T-cell therapy efficacy; accordingly, antibiotic exposure, which may induce dysbiosis, has been associated with inferior outcomes after CAR-T-cell therapy. Methods: We retrospectively analyzed clinical data from 140 patients to assess the impact of infection-related antibiotic therapy prior to CAR-T-cell therapy, stratifying them into two cohorts: 67 patients with previous antibiotic exposure and 73 without exposure. Results: Patients exposed to antibiotics prior to CAR-T therapy had significantly reduced progression-free survival (p = 0.016) and overall survival (p = 0.002) compared to those without exposure. Multiple antibiotic courses and shorter intervals between the last antibiotic treatment and CAR-T-cell therapy were linked to poorer outcomes. Conclusions: Our data suggest that pre-CAR-T-cell-therapy antibiotic exposure is associated with inferior outcomes, although it remains unclear whether this effect is causal or reflects underlying patient comorbidities. These findings highlight the need for further studies investigating the role of antibiotic-induced dysbiosis on CAR-T-cell therapy efficacy.