Several studies have demonstrated that ambroxol stimulates surfactant synthesis and has antioxidative and antiinflammatory effects. We investigated the effect of ambroxol on lung function in newborns with respiratory distress syndrome (RDS) weighing <1,500 g. In all, 102 newborns were enrolled (52 received ambroxol and 50 placebo). After extubation, lung function tests were performed weekly using a face mask for ventilatory measurements and a catheter tip pressure transducer (diameter 1.7 mm) for esophageal pressure measurements (Pes) The flow-through technique was used to eliminate apparatus dead space and to allow long-term measurements during quiet sleep. Percentile curves of pulmonary function parameters from healthy newborns were used for comparison. During the first 28 days, 42 newborns were extubated in the ambroxol group and 36 in the placebo group. The ventilatory parameters of both treatment groups were in the normal range and there were no significant differences between the two groups at any time. After extubation, the ratio of tidal volume to maximal esophageal pressure changes (V(T)/P(es,max)) was below the 10th percentile in the ambroxol and placebo-treated groups. In the ambroxol group the 10th percentile was reached on day 10, whereas in the placebo group the 10th percentile was reached significantly later (P < 0.05) on day 23. Modeling of power expenditures was used to identify the optimal breathing pattern so that small differences in ventilatory parameters between the two groups could be analyzed. We conclude that early ambroxol treatment has only a modest effect on lung function in newborns with established RDS. The sensitivity of tidal breathing parameters is not sufficient to detect these small changes in lung mechanics, but small improvements could be demonstrated in lung mechanics 10 days after extubation in the ambroxol-treated group.