The enzyme systems involved in the reduction of the narcotic antagonists, naloxone and naltrexone, were studied from the liver of chicken and rabbit. These secies were chosen because the relative amounts of diastereoisomeric products formed by enzymatic reduction between these species are so different; naloxone and naltrexone are converted in the chicken to 6alpha-naloxol and 6alpha-naltrexol, respectively, and in the rabbit to 6beta-naloxol and 6beta-naltrexol, respectively. In the present study, the enzymes for carrying out this reduction were found to require NADPH and to occur in the soluble fraction of liver homogenates. These enzymes were precipitated at 60-70% ammonium sulfate saturation for the chicken and at 50-60% for the rabbit. Differential sensitivity to inhibitors could be shown. For example, the rabbit enzyme was more sensitive to inhibition by morphine than was the chicken enzyme. The reverse order of sensitivity was seen with ketamine. These differences in properties between the chicken and rabbit liver enzymes indicate that the alpha- and beta-hydroxy product stereoselectivity arises from two different enzymes carrying out the reduction.