Previous studies in preterm lambs have shown that exogenous surfactant is more uniformly distributed if given at birth before ventilation or if followed by high-frequency ventilation (HFV) after establishing conventional ventilation (CV). We hypothesized that the pre-term rabbit pup would respond similarly and that improved respiratory system compliance (Crs) would accompany improved surfactant distribution. We randomized pups (27 d gestation) into three groups: control, surfactant at birth, and surfactant after 15 min of CV (rescue). We administered dipalmitoylphosphatidyl-[3H]choline-labeled natural surfactant by tracheostomy to each of the treated groups. The two treatment groups were treated for 15 min with either HFV or CV and subsequently with CV. We measured Crs at 15, 25, 35, and 45 min after surfactant. Lungs from pups treated with CV or HFV (n = 89) for 15 min, with and without 30 min of subsequent CV, were cut into 32 pieces that were counted for distribution of label or were sectioned for quantitative morphometry (n = 36). Pups receiving surfactant after 15 min of CV had higher Crs 15 min after surfactant than either pups treated with surfactant at birth or controls (p less than 0.001). The Crs of pups 15 min after rescue surfactant followed by HFV was lower than that of pups treated with CV (p less than 0.05) but was higher than that of either control or pups treated at birth groups (p less than 0.05). Crs at 35 and 45 min after surfactant were the same in all treatment groups. Application of HFV appeared to delay the delivery of surfactant to the distal airspaces.(ABSTRACT TRUNCATED AT 250 WORDS)