Human fetal kidney tissue was found to be rich in NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) activity. The enzyme activity was localized primarily in the medullary portion of fetal kidney. Separated cortical and medullary tissue fragments were maintained in organ culture for up to 9 days. The specific activity of PGDH in cortical tissue was low at the commencement of organ culture and remained low throughout the culture period. The specific activity of PGDH in medullary tissue fell precipitously during the first 48 h in organ culture; thereafter, the specific activity of the enzyme increased steadily during the culture period and reached values of up to ten times that in starting tissue by 6-7 days in organ culture. The decline in specific activity of PGDH in medullary tissue during the first 48 h in culture could be prevented by including inhibitors of lysosomal enzyme activity, i.e., chloroquine or ammonium chloride, in the culture medium. We suggest that human fetal kidney tissue explants in organ culture may be an appropriate model for the study of the regulation of PGDH activity. Such an evaluation of the regulation of PGDH is believed to be of importance since PGDH serves to regulate the levels of and, thence, the action of the biologically active prostaglandins.