Inflammation is often modeled with endotoxin (LPS from E. coli). Intracerebroventricular (ICV) infusion of appetite-stimulatory neuropeptides, many of which act “downstream” of leptin, and fasting inhibit LPS-induced reduction in feed intake and changes in body temperature. The objective of this study was to test the effects of a leptin receptor antagonist on LPS-induced hypophagia and fever in sheep. Adult black face ewes [n = 16; 81.2 ± 23.1 kg] were ovariectomized and fitted with a cannula for ICV infusion. Ewes were kept in individual pens with a 12-h light/dark photoperiod and ~22°C. Ewes had ad libitum access to a diet calculated to meet their requirements. Ewes received 1 of 2 treatments [0 (saline) or 500 (OLA; ovine super-active leptin antagonist) μg of OLA] administered via ICV infusion 30 min before receiving 1 of 2 peripheral treatments [0 (saline) or 0.4 (LPS; from E. coli O55:B5) µg/kg BW LPS] administered via the jugular vein. Feed intake and rectal temperature was determined at −72, −48, −24, 0, 2, 4, 6, 8, 12, 24, 36, and 48 h relative to peripheral treatments. Data were analyzed using repeated measures procedures with JMP software and tested for effects of LPS, OLA, and time, and all their interactions. As expected, LPS decreased feed intake at 2 and 4 h, but increased at 8 h compared with saline (LPS × time, P < 0.05). For ewes receiving LPS, OLA decreased feed intake at 2 h but increased at 12 h compared with saline (LPS × OLA × time, P = 0.07). Rectal temperatures were affected by LPS and OLA in a time-dependent fashion. LPS increased rectal temperatures at 2, 4, and 6 h (LPS × time, P < 0.0001) and OLA increased it at 6, 8, and 12 h (OLA × time, P < 0.0001), both compared with saline. We found no evidence that OLA moderated the hypophagic and febrile effects of LPS (OLA × LPS, P > 0.10). In contrast, OLA administration can increase rectal temperature in sheep.