Previous work revealed that portacaval anastomosis (PCA) in rats results in hepatic atrophy and marked decreases in components of the microsomal monooxygenase system such as cytochrome P-450. In the present study, the effects of PCA on hepatic monooxygenase activity were studied in more detail. We report that PCA, in general, produces effects resembling those of castration. Thus, in male rats, PCA depressed the activity of highly sex-dependent enzymes such as ethylmorphine and aminopyrine demethylases. Similar effects were produced by castration, and the combination of PCA and castration produced the same effect as either treatment alone. In male rats, non-sex-dependent enzymes such as aniline hydroxylase and NADPH-cytochrome c reductase were unaffected by either PCA or castration. By contrast, in female rats, neither PCA nor castration significantly affected microsomal monooxygenase activities. In male rats, PCA was accompanied by a 75% reduction in serum testosterone levels and a 6-fold increase in total estrogen levels. We conclude that these effects of PCA in male rats were due, in large measure, to a demasculinizing effect.