The aims of this study were to determine whether placental restriction (PR) alters the pattern of localization of the catecholamine-synthesizing enzymes, dopamine-β-hydroxylase and phenylethanolamine N-methyltransferase, and enkephalin (ENK)-containing peptides in the adrenal gland of the midgestation sheep fetus. We also determined the effect of PR on the content and profile of the molecular mass forms of ENK-containing peptides in the fetal adrenal medulla. Placental growth was restricted by removal of most of the placental implantation sites in the uterus before mating. In midgestation, placental and fetal body weight were reduced (p < 0.05) in the PR group (n = 8; 237.9 ± 39.5 g, 564.7 ± 41.6 g, respectively) when compared with the control group (n = 9; 479.1 ± 36.9 g, 721.2 ± 22.8 g, respectively). However, combined fetal adrenal weight and adrenal cortical and medullary area were similar in the PR and control fetuses. In PR fetuses, distribution of staining for dopamine-β-hydroxylase, phenylethanolamine N-methyltransferase, and ENK-containing peptides in the adrenal medulla was similar when compared with the control group; however, staining was less intense and not all adrenomedullary cells were stained. The total adrenal content of ENK-containing peptides was also significantly (p < 0.05) less in the PR group (103.4 ± 18.6 ng/adrenal) than in the control group (243.6 ± 24.8 ng/adrenal). However, the molecular mass profile of ENK-containing peptides was not altered in the PR fetuses compared with controls. These data suggest that placental restriction in utero may alter the synthesis and/or secretion of catecholamines and ENK-containing peptides from the fetal adrenal medulla from as early as 90 d gestation.