<p>Patients with acute leukemia undergoing induction chemotherapy are at high risk of infectious complications. Fluoroquinolone prophylaxis is used to reduce bacterial infections, but concerns persist regarding antimicrobial resistance and overall clinical benefit. This study evaluated the impact of levofloxacin prophylaxis during induction chemotherapy for acute leukemia. This prospective randomized study included adult patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) undergoing induction chemotherapy. Patients were randomized to receive either levofloxacin prophylaxis or no prophylaxis. Infectious outcomes, antibiotic utilization, antimicrobial resistance, invasive fungal infections (IFI), and induction mortality were assessed. A total of 130 patients were included (AML, n=70; ALL, n=60), randomized equally to levofloxacin and control arms. Levofloxacin prophylaxis significantly reduced microbiologically documented infections in AML (20% vs 34%; p=0.002) and ALL (20% vs 30%; p=0.03), as well as bloodstream infections in AML (17.4% vs 28.4%; p=0.014). Duration of intravenous antibiotic therapy was reduced in AML (10 vs 13 days; p=0.018) and ALL (12 vs 14 days; p=0.042). Gram-negative infections were lower with prophylaxis, but fluoroquinolone resistance among isolates was higher (77.7% vs 50%; p=0.007). Invasive fungal infections incidence and time to antifungal initiation were similar between groups. Induction mortality was comparable between levofloxacin and control arms in AML (17.1% vs 17.1%) and ALL (10% vs 13.3%). Levofloxacin prophylaxis reduces bacterial infections and antibiotic exposure during induction chemotherapy in acute leukemia but does not improve survival and is associated with increased fluoroquinolone resistance. Judicious use guided by local resistance patterns is warranted. </p>