We compared ceftazidime monotherapy with ceftriaxone/tobramycin in a prospective, randomized clinical trial that included 580 patients with serious hospital-acquired infections. One-half of the patients had an underlying disease with a rapidly or ultimately fatal prognosis; 40% were nursed in intensive care units. Clinical response among patients with pneumonia (73% in the ceftazidime group vs. 65% in the ceftriaxone/tobramycin group), septicemia (73% vs. 59%), and complicated urinary tract infections (80% vs. 76%) showed that there were no significant differences in efficacy between the two regimens. Pseudomonas aeruginosa was the most prevalent pathogen and was effectively eradicated by both treatments. The odds of bacteriologic cure with either study regimen were equal. Mortality was similar in both treatment groups. Ceftazidime monotherapy was not associated with a higher incidence of development of resistance or superinfection. Both regimens were well tolerated; no patients receiving ceftazidime evidenced nephrotoxicity, compared with nine who received the combination. We conclude that ceftazidime may be used as monotherapy in the empirical treatment of patients with serious nosocomial infections.