We present our experience in patients with hematologic malignancy and infection treated with ceftolozane-tazobactam. We performed a single-center case-control study comparing patients with hematologic malignancy and infection treated with ceftolozane-tazobactam (study group) with similar patients not treated with ceftolozane-tazobactam (control group) to assess safety and efficacy. Nineteen cases and 38 controls were analyzed. Cases were younger (45.6 years versus 57.6 years;  = 0.012) and less frequently had bacteremia (52.6% versus 86.8%;  = 0.008). They also had worse Multinational Association for Supportive Care in Cancer (MASCC) scores (10.2 versus 16.1;  = 0.0001), more hospital-acquired infections (78.9% versus 47.4%;  = 0.013), and more extremely drug-resistant (XDR) infections (47.4% versus 21.1%;  = 0.015). Cases received a median of 14 days (7 to 18 days) of ceftolozane-tazobactam (monotherapy in 11 cases 57.9.6%). Ceftolozane-tazobactam was mostly used as targeted therapy (16 cases; 84.2%) because of resistance (9 cases; 47.4%), failure (4 cases; 21.1%), and toxicity (3 cases; 15.8%). Ten cases had bacteremia (52.6%). The sources were pneumonia (26.3%), catheter-related bacteremia (21.1%), primary bacteremia (21.1%), and perianal/genital (15.7%), urinary (10.5%), and skin/soft tissue (5.3%) infection. No toxicity was attributed to ceftolozane-tazobactam. More than 60% had neutropenia, and 15.8% fulfilled the criteria for sepsis. There were no significant differences in clinical cure at day 14 (89.5% versus 71.1%;  = 0.183) or recurrence (15.8% versus 10.5%;  = 0.675). Thirty-day mortality was lower among cases (5.3% versus 28.9%;  = 0.045). Ceftolozane-tazobactam was well tolerated and at least as effective as other alternatives for infection in patients with hematologic malignancy, including neutropenic patients with sepsis caused by XDR strains.