20α-Hydroxysteroid oxidoreductase (20α-HSDH) activity and 20α-dihydroprogesterone concentration (20α-DHP) reach peak values in the human placenta after vaginal delivery. To determine if these findings are unique to the human, we measured 20α-HSDH activity as well as endogenous progesterone (P) and 20α-DHP concentration in the soluble supernatant fraction of placental tissues obtained from rodents (rat, rabbit, guinea pig), ungulates (horse, zebra, giraffe, cow), and primates (squirrel monkey, orangutan, man). P concentration was very low in rodents (mean 0.60 ng/mg protein), increased slightly in ungulates (mean 2.89 ng/mg protein), and reached a maximum value in the human (34.43 ng/mg protein) 20α-DHP concentration had a strong positive correlation (r = 0.93) with P tissue content; it was low in rodents (mean 0.21 ng/mg protein), increased slightly in ungulates (mean 0.79 ng/mg protein), and reached a maximum value in the human (39.53 ng/mg protein). 20α-HSDH activity, however, had a poor correlation with 20α-DHP tissue concentrations: Its lowest value was in the guinea pig (9.34 pmole/mg protein/hour) and the highest was in the horse (3.19 nmole/mg protein/hour). These results indicate that a high level of activity of the P to 20α-DHP pathway with significant tissue accumulation of 20α-DHP is unique to the human placenta and reinforce the possibility of its causing in situ P withdrawal as a part of the overall mechanism of human parturition. © 1979.