The multiple-dose pharmacokinetics and toleration of cefoperazone (3 g every 12 h) and sulbactam (1.5 g every 12 h) were studied when these antimicrobial agents were administered continuously over 7 days as a 15-min infusion of individual agents and as a 3/1.5-g cefoperazone-sulbactam combination. Fourteen male volunteers participated in an open, three-way crossover study of Latin Square design with a 1-week washout period between phases. On days 1 and 7 of each phase, serial serum samples and urine were collected for drug assay over a 12-h period. Hematological and clinical chemistry determinations were made within 10 days before the first antibiotic dose and for each treatment phase just before the first dose, on day 4 of treatment, and within 24 h of the last dose. For cefoperazone as a single agent on days 1 and 7, the average maximal concentration in serum (Cmax) was approximately 430 micrograms/ml, the terminal elimination half-life (t1/2) was 1.8 h, and the average percentage of dose excreted unchanged in the urine (%Ur) was 30%. For sulbactam as a single agent, the Cmax was approximately 90 micrograms/ml, the t1/2 was 1 h, and the %Ur was 89% on days 1 and 7. When comparing individual versus simultaneous drug administration, the only pharmacokinetic alteration observed was a statistically significant but minor (about 10%) decrease in sulbactam renal clearance, on both days 1 and 7, resulting in a similar decrease in total body clearance (CL). The area under the curve, apparent volume of distribution by the area method (V), t1/2, and Cmax were not significantly altered. Although cefoperazone pharmacokinetic parameters were not significantly altered when comparing single-agent to combination drug administration, the area under the curve was slightly lower and CL, nonrenal clearance, and V were modestly higher from day 1 to day 7. Because Cmax and t1/2 were unaffected, these minor day effects would not be of clinical significance. Intravenous administration of cefoperazone and sulbactam given as individual agents compared with the combination did not show pharmacokinetic differences that are likely to produce clinically relevant effects. The combination of cefoperazone and sulbactam was well tolerated, and the safety profile of the combination was similar to that either drug given alone under the conditions of this study.