<i>Background:</i> There is insufficient data to reliably assess the benefit of bronchodilators in ventilated premature neonates. <i>Objectives:</i> To compare the efficacy/tolerance of inhaled ipratropium bromide (IB) vs. terbutaline (T) and to describe factors associated with their efficacy. <i>Methods:</i> A cross-over randomized controlled double-blind trial including intubated neonates with respiratory distress syndrome. Two puffs of IB or T were administered at 0, 20, 40 min. Passive respiratory system resistance (Rrs) and compliance (Crs) were measured at 0, 20, 40, 60 min. A positive response was defined as a >2 individual coefficients of variation decrease in Rrs or increase in Crs. <i>Results:</i> Twenty-one infants (gestational age (mean ± SD): 27.3 ± 1.6 weeks; birth weight: 947 ± 250 g; postnatal age: 20 ± 9 days) were included. At 60 min, no treatment effect for Rrs and Crs could be identified (cross-over analysis). Overall data (irrespective of order of administration) showed that after 6 puffs, the decrease in Rrs was greater in the IB vs. T group (–17.0 ± 22.2% vs. –11.3 ± 26.7%, respectively (NS)). Thirty-eight percent of infants responded to IB vs. 43% to T. However, in 19% of patients, decreased Crs was observed after 6 puffs of T. No marker of a positive or paradoxical response could be identified. Treatment was well-tolerated. <i>Conclusion:</i> High doses of bronchodilators are required in ventilated neonates, but the positive response rate was <50%. Their long-term benefit remains to be proven.