The double beta-lactam combination of cefoperazone plus piperacillin was compared with an aminoglycoside-containing regimen of mezlocillin plus tobramycin in a prospective, randomized trial of empiric therapy for febrile neutropenic patients (neutrophils no more than 1,000/mm3). Thirty febrile episodes were treated with cefoperazone plus piperacillin and mezlocillin plus tobramycin, respectively. There was no significant difference between the two groups with respect to age, sex, pretherapy neutrophil count, and mean duration of therapy. The majority of patients had neutrophil counts of no more than 200/mm3 at the initiation of therapy. Only microbiologically and clinically documented infections were evaluated for efficacy. The cefoperazone plus piperacillin regimen appeared to have a comparable response rate with the mezlocillin plus tobramycin regimen (20 of 24 patients [83 percent] versus 16 of 23 patients [70 percent]). Gram-positive micro-organisms were seen predominantly in this study, with the cefoperazone plus piperacillin regimen achieving a bacteriologic response in 84 percent, as opposed to 60 percent for those organisms treated with the mezlocillin plus tobramycin regimen. Neither regimen was totally effective against coagulase-negative staphylococci. Eight superinfections occurred in the cefoperazone plus piperacillin arm, whereas 11 superinfections occurred in the mezlocillin plus tobramycin arm. Although fungal superinfections were most common, the number of gram-positive superinfections in the mezlocillin plus tobramycin arm exceeded those seen in the cefoperazone plus piperacillin arm. The incidence of antibiotic-related side effects was similar in the two groups. Hypokalemia was most frequently seen. Both skin rashes and nephrotoxicity were more common with mezlocillin plus tobramycin. Cefoperazone plus piperacillin was found to be effective empiric therapy in febrile neutropenic patients. This double beta-lactam combination may be particularly useful for patients who have or are at high risk for the development of renal insufficiency.