Abstract The constant occurrence of increased feed intake in offspring exposed to intrauterine growth restriction has been noted across multiple species including ruminants. In ruminants, reduced circulating leptin concentrations from birth through the first week or two of life may influence the development of the appetite center of the hypothalamus. It should able be noted that increased circulating cortisol at birth has been associated with this decreased circulating leptin in the perinatal ruminants, yet information is limited as to any cause and effect relationship between the two hormones. The objectives of these studies were to test directly the effects of exogenous cortisol on leptin concentrations relative to development of the hypothalamus in perinatal calves and voluntary feed intake as yearling. In two experiments, Holstein bulls (n = 27) and calves (n = 32 males; n = 30 females) from commercial Angus cows were assigned to treatments at parturition (day 0). Calves were intravenously infused with either a low cortisol [LC; n = 9, 3.5 ug/kg of body weight (BW)], high cortisol (HC; n = 9, 7.0 ug/kg BW), or a control (CON; n = 9, saline). Calves were administered a half dose of their respective treatment 24h postpartum. Jugular vein blood samples were collected before infusion and daily until d 17 or necropsy. At 5 days of age Holstein bull calves were euthanized where cerebral-spinal fluid (CSF) and hypothalamic tissue were collected. Serum and CSF leptin concentrations were analyzed via RIA. Neuronal growth factors were analyzed in hypothalamus samples via qRT-PCR. In experiment 2, yearling calves entered a GROWSAFE System and daily feed intake (FI) measured. Animals were allowed a two-week adjustment period to a growing ration for heifers and a finishing ration for steers. Heifer body condition scores (BCS) were collected at the beginning and end of the trial. Heifers underwent the feeding trial for 70 days and steers until they obtained a back fat (BF) thickness of 1.15 cm. Blood samples were analyzed similar to experiment 1. All data were analyzed via repeated measures using appropriate models of SAS (SAS Institute Inc., Cary, NC). Perinatal dairy bull calves had decreased (P < 0.013) serum and CSF leptin concentrations of HC and LC calves compared with CON. Hypothalamic expression of BDNF, FGF1 and FGF2 were decreased (P < 0.006) in HC and LC compared with CON. During the feeding trial: BW gain, BCS change, and number of feed events were increased (P = 0.001) in LC compared with HC and CON heifers. However, LC observed greater daily FI (P = 0.047) and tended to have greater final BW (P = 0.080) compared with HC and CON steers. In summary, these data support that exogenous cortisol administered to perinatal calves affects leptin production and the appetite center of the hypothalamus when administered during the neonatal period.