A prospective cohort study enrolling 107 infants weighing less than 1250 g was conducted between September 1, 1986, and November 15, 1987 in order to determine the role of microorganisms on the development of chronic lung disease (CLD). Ureaplasma urealyticum was isolated significantly more frequently from gastric aspirates and nasopharyngeal or endotracheal aspirates from 43 infants developing CLD than from 56 who did not (51% vs. 16%; P less than 0.005). Infants developing CLD, defined by radiographic and blood gas abnormalities, were significantly younger (26 vs. 29 weeks; P less than 0.0001), weighed significantly less (830 vs. 1050 g; P less than 0.0001) and required more ventilatory support (37 vs. 10 were being ventilated and 42 vs. 26 received oxygen supplementation on Day 7) compared with those who did not develop CLD. Viruses were isolated in association with U. urealyticum in two infants developing CLD and in one infant who did not develop CLD. Mycoplasma hominis was isolated from three infants who were colonized with U. urealyticum and developed CLD. Chlamydia trachomatis was not recovered from any patients. From a discriminant analysis it was found that U. urealyticum contributed to the development of CLD along with the effect of ventilatory support, gestational age and severity of initial respiratory disease. The effect of interventions directed against U. urealyticum on the development of CLD deserves further study.