Twenty-nine patients with cystic fibrosis received either cefsulodin or a reference agent (tobramycin or ticarcillin) in a randomized manner for treatment of pulmonary infections associated with Pseudomonas aeruginosa. Patients ranged in age from 12 to 30 years. Their infections were classified as mild (six), moderate (16), or severe (seven). Fourteen patients received cefsulodin, 14 patients were treated with tobramycin, and one patient received ticarcillin. Significant clinical improvement was noted in the majority of patients in both groups. Adverse effects and development of laboratory abnormalities were uncommon in both groups. P. aeruginosa was not permanently eradicated from the sputum of any of the patients. Resistance as measured by disk susceptibility testing may have developed during and immediately after therapy in the cefsulodin group but not in those treated with reference agents. However, this did not appear to affect the clinical outcome. Results of the nonrandomized portion of this multicenter study, in which 46 patients were treated with cefsulodin, were similar to those for the randomized group. Thus, cefsulodin was shown to be as clinically effective as the reference agents in the treatment of lower respiratory tract infections due to Pseudomonas aeruginosa in patients with cystic fibrosis.