This study determined whether feeding the immunomodulating supplement, OmniGen-AF, to feedlot heifers would alter metabolic profiles to a glucose tolerance test. Heifer calves (n = 32; 217 ± 2 kg) were allocated into two treatment diets: 1) Control, fed a standard receiving ration, and 2) OmniGen, fed the Control diet supplemented with OmniGen at 4.54 g/45 kg BW/d. Heifers were fed for 42 d. On d 42, Heifers were processed through a working facility for placement of indwelling jugular catheters. After these procedures, heifers were moved into individual stanchions in an enclosed barn and all heifers were fed their treatment diets at 1400 h. All orts were removed at 2000 h to allow for a 12-h fast prior to first blood collection. The following day, heifers were administered 0.5 mL/kg BW of a 50% dextrose solution at 0900 h (0 min). Blood samples were collected for serum isolation at −60, −45, −30, −15, 0, 10, 20, 30, 45, 60, 90, 120, and 150 min relative to bolus dextrose infusion. Serum was stored at −80 oC until analyzed for cortisol, glucose, insulin, non-esterified fatty acid (NEFA) and urea N concentrations. There was a treatment × time interaction for post-challenge cortisol (P = 0.004) such that cortisol was greater in OmniGen heifers than Control heifers from 10- to 45- min post-infusion. Glucose concentrations increased post-infusion (P < 0.01) and were reduced in OmniGen compared to Control heifers at 10-, 45-, and 90-min after challenge (treatment × time P < 0.001). Similarly, there was a treatment × time interaction for post-challenge insulin concentrations (P = 0.04) such that insulin was greater in OmniGen-fed heifers than Control heifers from 10 to 30 min. In addition, there was a treatment × time interaction (P = 0.01) for NEFA concentrations such that concentrations were reduced in OmniGen-supplemented heifers from 10 to 30 min following administration of the dextrose bolus. Serum urea N concentrations were greater in Control heifers at 150 min compared to OmniGen-fed heifers (post-challenge treatment × time interaction: P < 0.001). These data suggest that OmniGen-fed heifers were more responsive to changes in glucose, perhaps affecting the storage and/or redistribution of energy deposits and provide further evidence for altered metabolism in OmniGen-supplemented cattle. The differences observed may explain differences observed in the immune response in OmniGen-supplemented calves.