To assess the efficacy of once daily monotherapy relative to standard combination antibiotic therapy for the initial management of patients suspected of serious bacterial infections, we conducted a randomized trial comparing ceftriaxone (Rocephin®) with a combination of cefuroxime plus gentamicin. Of 105 patients, 53 were treated with ceftriaxone alone and 52 with the combination; 13 patients were considered not evaluable. 42 of 53 patients given ceftriaxone and 33 of 52 given cefuroxime plus gentamicin responded to treatment (p = 0.07). Three patients given ceftriaxone and 6 who received gentamicin plus cefuroxime died (p = 0.28). Definite bacterial infections were identified in 67 patients; of the evaluable patients with a definite infection 27 of 29 who received ceftriaxone and 21 of 31 who were treated with the combination were cured (p = 0.01). No difference was found in the number of side effects. However, therapy had to be discontinued due to treatment failure, an adverse effect or death in 1 of 33 patients given ceftriaxone and in 11 of 34 given the combination (p = 0.002). Ceftriaxone was found to have an impact on the count of E. coli in intestinal microflora. Changes in normal bacterial composition did not lead to the overgrowth with resistant Enterobacteriaceae or Pseudomonas, however, colonization by yeast was observed. Using ceftriaxone reduced the cost of antimicrobial therapy per patient by 107 £ (US$ 183). Moreover, the total time saved per patient due to decreased nursing and drug administration time per day was 40 min. We conclude that monotherapy with ceftriaxone, 2 g administered once daily, is at least as effective and provides cost and time savings compared to the combination regimen of gentamicin plus cefuroxime for the initial treatment of patients in our institution with serious systemic bacterial infection