The inactivation of prostaglandin E2 (PGE2) was studied in isolated perfused lungs of fetal and neonatal rabbits. 200 nmol of 14C-PGE2 was infused into the pulmonary circulation and the metabolites of PGE2 were analysed from the nonrecirculating perfusion effluent. The amount of the main metabolite, 13,14-dihydro-15-keto-PGE2, increased significantly between the 28th and 30th day of fetal life, remained relatively constant at the time of birth and increased again between 1st and 7th postnatal day. In contrast, the amount of 15-keto-PGE2 remained relatively stable during the studied period. The activity of NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-OH-PGDH) was determined from the 100.000 g supernatant fraction of fetal, neonatal and maternal rabbit lungs using 14C-PGE2 (20 microM) as the substrate. In the lungs of late fetal rabbits the activity of 15-OH-PGDH was significantly higher compared to the early postnatal period. Maternal rabbit lungs possessed, however, very high activities compared to the studied perinatal lungs. The results show, that the activity of the pulmonary 15-OH-PGDH is high already during the late fetal period. The inactivation of PGE2 in isolated perfused lungs seems, however, to increase during the last prenatal days. Thus it seems possible that the uptake mechanism could be the rate limiting step in the metabolism of PGE2 in rabbit lungs during the perinatal period.