To evaluate the effect of intratracheal administration of N-acetylcysteine (Mucomyst) on the clinical status, pulmonary function and gas exchange in premature infants with chronic lung disease, we conducted a randomized, placebo-controlled, crossover trial. Ten mechanically ventilated infants (gestational age 27 +/- 1 week; postnatal age 22 +/- 6 days) with clinical and radiological evidence of chronic lung disease and increased airway secretion were enrolled in the study. Each infant received tracheal administration of 5% N-acetylcysteine for one week and saline placebo every 4 h for another week. N-acetylcysteine was associated with a 59 +/- 26% increase in total airway resistance by the third day of treatment (p less than 0.01). A two-fold increase in airway resistance associated with an increased frequency of bradycardia and cyanosis spells was seen in two of the infants following three days of N-acetylcysteine administration, with a rapid improvement in their condition when subsequently switched to saline. Overall, N-acetylcysteine administration had no effect on the variables measured. We conclude that intratracheal administration of N-acetylcysteine to liquefy airway mucus neither improves the clinical condition nor hastens recovery in premature infants with chronic lung disease and its administration may lead to increased total airway resistance and cyanotic spells. The present data do not support the use of N-acetylcysteine as a mucolytic agent in premature infants with chronic lung disease.