Pregnancy in Thamnophis elegans is associated with an increase in the nucleoside triphosphate (NTP) concentration and a concomitant decrease in the oxygen affinity of the adult red cell. Red cell NTP levels rise at about the time of ovulation and peak during mid-gestation. Since plasma progesterone levels appear to have a similar profile, we examined the influence of progesterone on this phenomena. Surgical removal of the corpora lutea (CL), primary site of progesterone release, plus fetuses abolished the pregnancy-associated effect on red cell NTP levels. Removal of the CL alone resulted in NTP levels intermediate to those of the red cells of the nonpregnant and the pregnant groups. Progesterone implants in nonpregnant females, as well as in males, caused red cell NTP concentrations to rise. These data support the hypothesis that progesterone, secreted by the CL, in the presence of the fetus, is largely responsible for the pregnancy-associated increase in the red cell NTP concentration.