Although surfactants containing only lipids and surfactant protein C (SP-C) or SP-C analogs can be effective for the treatment of surfactant deficiency in animal models, there is no information concerning the alveolar or lung clearance of SP-C. Because the other lipid and protein components of surfactant are cleared very slowly from the preterm lung, we hypothesized that SP-C also would be cleared slowly. Therefore, we compared the losses of iodinated native SP-C (nSP-C) and recombinant SP-C analog (rSP-C, phenylalanines in positions 4 and 5 and isoleucine in position 32 of the human sequence) to [14C] dipalmitoylphos-phatidylcholine (DPPC) after airway administration at birth of trace or treatment doses of surfactant given to preterm lambs. In preterm lambs given trace doses at 134-136 d gestation, alveolar [14C]DPPC and [125I]rSP-C decreased to 14.7% recovery for DPPC and 8.3% recovery for rSP-C after 2 h ventilation. There was no loss of [14C]DPPC from the total lungs (alveolar wash + lung tissue), and approximately 20% of the [125I]rSP-C was lost from the lungs. For 128 d gestational age lambs treated with 100-mg/kg doses of surfactants containing nSP-C or 2% of rSP-C, the alveolar and total lung recoveries for [125I]nSP-C or [125I]rSP-C were equivalent to that of [14C]DPPC after 5 h ventilation. These results demonstrate that nSP-C and rSP-C have alveolar clearances and accumulations into preterm lung tissue that are similar to those of DPPC.