Plasma concentrations of 17-alpha-hydroxyprogesterone caproate (17-OHPC) vary substantially in pregnant patients who receive an identical dose. Endogenous steroid hormones may alter 17-OHPC metabolism, which contributes to this large variability.Pooled human liver microsomes were incubated with 17-OHPC alone or in combination with progesterone, hydroxyprogesterone, estrone, estradiol, or estriol. High-performance liquid chromatography with ultraviolet detection was used to quantify 17-OHPC.Under the conditions that were studied, 17-OHPC metabolism was inhibited by 37% by a combination of endogenous steroid hormones. Progesterone alone significantly inhibited 17-OHPC metabolism by 28% (P < .001).17-OHPC metabolism is inhibited significantly by endogenous steroids and, in particular, progesterone. This effect may account for some of the large variation in plasma 17-OHPC concentrations that is seen in pregnant patients who receive a fixed dose of medication.