Female Wistar rats were treated with various doses of progesterone orally via the diet or via the SC route. Oral treatment resulted in enhanced progesterone levels in the liver as measured by radioimmunoassay. There were up to 3-fold increases in activity of ethylmorphine demethylation by isolated microsomes; metabolism of aminopyrine and benzphetamine was less enhanced, that of aniline and p-nitroanisol showed no distinct increases. Progesterone also caused increases in liver size and total liver protein by up to 50%; total liver DNA showed only slight, insignificant increments. These studies suggest that hepatic effects of progesterone are similar to those previously described with synthetic steroids such as pregnenolone-16 alpha-carbonitrile (PCN) and cyproterone acetate.