Objective: To compare the safety and efficacy of cefoperazone plus sulbactam (CPZ + SB) (3 g [2:1] every 8 h) and ceftazidime (CTZ) (2 g every 8 h) as monotherapy in the empiric treatment of febrile neutropenia in patients with cancer. Patients: One hundred eighteen cancer patients with chemotherapy-associated neutropenia and fever. Most patients (82) received norfloxacin and fluconazole as prophylaxis. Results: Fifty-nine patients were enrolled in the CPZ + SB group, and 59 were enrolled in the CTZ group. The mean duration of antibiotic therapy was less than 10 days in both groups. Forty-three patients (19 in the CPZ + SB group and 24 in the CTZ group) were bacteremic, and 7 others had cellulitis. Of the 56 microorganisms producing bacteremia, 51 were gram-positive bacteria, mostly staphylococci (28 isolates) and streptococci (22 isolates). Gram-positive cocci were more frequently resistant to CTZ than to CPZ + SB (77% vs. 40%, respectively; p < 0.002). However, the clinical response rate at 72 hours of therapy was 53% in the CPZ + SB group and 52% in the CTZ group (p = 1.0). At the end of therapy, clinical responses were similar in the two groups (p = 0.19). Clinical success with antibiotic modification was seen in 42% of the CPZ + SB recipients and in 58% of CTZ recipients (p = 0.10). Bacteriologic eradication among bacteremic patients appeared to be slightly better in the CPZ + SB group (79% vs. 54%; p = 0.09). Except for rashes in 3 patients (1 in the CPZ + SB group and 2 in the CTZ group), both drugs were well tolerated. Adverse events included superinfections, transient elevation of serum transaminase concentrations, diarrhea, and chills. Conclusions: CPZ + SB was superior to CTZ in its in vitro activity against aerobic gram-positive cocci encountered in the study; however, the clinical efficacy and safety of the two drug treatments were similar in the empiric therapy for febrile neutropenia.