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Abstract Background With increased use of antibiotics in high risk patients, the investigation of new antibiotics to cover potentially resistant pathogens is warranted. In this prospective randomized trial (NCT03485950), we compared ceftolozane/tazobactam (C/T), a new cephalosporin/β-lactamase inhibitor, to the standard-of-care (SOC) for the empiric treatment of neutropenia and fever in patients with hematological malignancies. Methods We enrolled 100 patients to receive intravenous (IV) C/T or SOC antibiotics (cefepime, piperacillin/tazobactam, or meropenem) in combination with gram-positive antibacterial agents. We evaluated responses at the end of IV therapy (EOIV), test of cure (TOC; days 21-28), and late follow-up (LFU; days 35-42). Results We analyzed 47 C/T patients and 50 SOC patients. C/T patients had a higher rate of favorable clinical response at EOIV (87% vs 72%). A one-sided non-inferiority analysis indicated that C/T was at least not inferior to the SOC for favorable clinical response at EOIV (p=0.002), TOC (p=0.004) and LFU (p=0.002). Superiority tests showed that C/T led to significantly lower rates of clinical failure at TOC (6% vs 30%; p=0.003) and LFU (9% vs 30%; p=0.008). C/T and SOC patients with documented infections had similar rates of favorable microbiological response. Serious adverse events leading to drug discontinuation (2% vs 0%; p=0.48), and overall mortality (6% vs 4%; p=0.67) were similar in both groups. Conclusions The empiric use of C/T in high-risk patients with hematological malignancies and febrile neutropenia is safe and associated with better clinical outcomes than SOC antimicrobial agents.