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The empirical treatment of febrile, neutropenic patients with cancer requires antibacterial regimens active against both gram-positive and gram-negative pathogens. This study was performed to demonstrate the noninferiority of monotherapy with piperacillin-tazobactam, compared with cefepime.We conducted a randomized-controlled, open-label, multicenter clinical trial among high-risk patients from 34 university-affiliated tertiary care medical centers in the United States, Canada, and Australia who were undergoing treatment for leukemia or hematopoietic stem cell transplantation and were hospitalized for empirical treatment of febrile neutropenic episodes. Patients received piperacillin-tazobactam (4.5 g every 6 h) or cefepime (2 g every 8 h) intravenously. The primary outcome was success (defined by defervescence without treatment modification) at 72 h of treatment, end of treatment, and test of cure in the modified intent-to-treat analysis. Secondary outcomes included time to defervescence, microbiological efficacy, the additional use of glycopeptide antibiotics, emergence of resistant bacteria, and safety.For 528 subjects (265 received piperacillin-tazobactam and 263 received cefepime), success rates were 57.7% and 48.3%, respectively (P = .04) at the 72-h time point, 39.6% and 31.6% (P = .06) at end of treatment, and 26.8% and 20.5% (P = .11) at the test-of-cure visit. The analyses demonstrated noninferiority for piperacillin-tazobactam at all time points (P ≤ .0001). Treatment with piperacillin-tazobactam was independently associated with treatment success in multivariate analysis (odds ratio, 1.65; 95% confidence interval, 1.04-2.64; P = .035). Both regimens were well tolerated.This study demonstrates the noninferiority and safety of piperacillin-tazobactam monotherapy, compared with cefepime, for the empirical treatment of high-risk febrile neutropenic patients with cancer.