Nineteen patients with pulmonary exacerbations of cystic fibrosis due to Pseudomonas aeruginosa were given imipenem/cilastatin for six to 10 days at dosages of 30-90 mg/kg per day. Mean Shwachman scores rose from 46.6 to 50.3 (P less than .001), clinical efficacy scores from 34.3 to 43.3 (P less than .001), vital capacity from 53.7% to 58.5% of the predicted value (P less than .01), forced expiratory volume in 1 sec from 39.5% to 42.6%, and partial pressure of oxygen in arterial blood from 68.2 mm Hg to 72.6 mm Hg. Treatment failed in only two instances. The concentration of P. aeruginosa in the sputum decreased to a modest extent (8.5 log10 cfu/ml on day 1, 8.1 log10 cfu/ml on day 10; P greater than .1). Four patients had imipenem-resistant strains of P. aeruginosa at the start of therapy, and 11 additional patients developed resistant strains during treatment; in eight patients greater than 90% of all Pseudomonas organisms in the sputum were resistant at the end of therapy. Six patients acquired Candida in their sputum. There was no correlation between bacteriologic improvement or the development of resistance to imipenem and either clinical outcome or improvement in pulmonary function. In summary, imipenem/cilastatin therapy is associated with a good clinical outcome in patients with cystic fibrosis, but resistance emerges rapidly.