BACKGROUND An association between recovery of Ureaplasma urealyticum from the respiratory tract of very low birth weight (VLBW) infants (< or =1500 g) and later chronic lung disease (CLD) was reported by several authors before the routine use of exogenous surfactant (SURF). We sought to assess whether this relation persists in the era of routine SURF. METHODS We prospectively studied a cohort of 105 VLBW infants who required mechanical ventilation at < 12 h of age. Tracheal aspirates for U. urealyticum culture were obtained before administration of SURF or antibiotics. Clinicians were unaware of U. urealyticum status. Chest radiographs at 28 days were reviewed by a single pediatric radiologist, blinded to U. urealyticum status. Sample size was predetermined to detect a 30% increase in CLD among those with U. urealyticum recovery from tracheal culture (U. urealyticum-positive) with alpha <0.05 and beta <0.20. RESULTS Of the study infants 22 were U. urealyticum-positive and 83 were U. urealyticum-negative. No differences were found between the groups for birth weight, gestational age, gender, inborn, antenatal or postnatal steroid use, SURF therapy, non-U. urealyticum infection, necrotizing enterocolitis, patent ductus arteriosus, intraventricular hemorrhage or cystic periventricular leukomalacia. At 28 days U. urealyticum-positive patients were significantly more likely to have CLD than U. urealyticum-negative [15 of 22 (68%) vs. 30 of 83 (36%); P < 0.02]. The U. urealyticum-positive patients also required significantly longer courses of supplemental oxygen and mechanical ventilation. No significant differences were found for CLD at 36 weeks postconception or duration of hospitalization, although type II error could not be excluded for these secondary endpoints. CONCLUSIONS Respiratory U. urealyticum at or shortly after birth remains associated with CLD at 28 days despite routine use of SURF. Controlled trials of anti-Ureaplasma therapy in U. urealyticum-positive VLBWs as soon after birth as possible may determine whether CLD, duration of respiratory support and attendant costs can be decreased.