Previous research indicates that early weaning before shipment can reduce transportation-induced increases in acute-phase proteins (APP) and can increase feedlot performance in beef calves. These data suggest that the combination of weaning and transport stress may compromise the immune system of calves, thus hindering subsequent performance and health. Therefore, our objective was to determine if the innate immune response of early weaned calves (EW; 80 d of age) differed from normal-weaned calves (NW; 250 d of age) in response to an endotoxin challenge. Eighteen Brahman x Angus calves (8 and 10 EW and NW, respectively; 233 +/- 5 kg of BW) were used. Calves were maintained on pasture with supplement and then moved into individual pens for 1 wk of acclimation before the start of the study. Calves were fitted with an indwelling jugular catheter 1 d before LPS challenge (0 h; 1.0 microg/kg of BW, intravenously). Blood samples were collected at 30-min intervals from -2 to 8 h. Serum samples were stored at -80 degrees C until analyzed for cortisol, tumor necrosis factor-alpha (TNF), IL-1 beta, IL-6, interferon-gamma (IFN), ceruloplasmin, and haptoglobin. Whereas LPS increased serum cortisol (P <or= 0.001), no weaning age effect (P >or= 0.15) was observed. A weaning age x time interaction (P <or= 0.04) was observed for TNF, IL-1, IL-6, and ceruloplasmin such that concentrations of these indices were greater in the NW compared with EW calves. For haptoglobin, a weaning age effect (P <or= 0.03) was observed with NW calves having greater average haptoglobin concentrations compared with EW calves. Interestingly, the weaning age x time interaction (P <or= 0.001) for IFN revealed greater IFN in EW compared with NW calves. Based upon these data, the innate immune system of EW calves appears to be more competent in responding to immune challenge compared with that of NW calves. Additionally, the differential IFN response indicates that the immune system of EW calves may be more effective at recognizing and eliminating endotoxin. These data suggest that an altered innate immune system may be one of the factors responsible for the improved feedlot performance previously reported in EW calves.