A subpopulation of calves, herein termed "hyper-responders" (HPR), was identified and defined by the patterns of plasma TNF- concentrations that developed following two challenges with endotoxin (LPS, 0.8 µg E. coli 055:B5 LPS/kg^0.75 live body weight) separated by 5 days. The principle characteristic of HPR-calves was a failure to develop tolerance to repeated LPS challenge that was evident in the magnitude of the TNF- concentrations and prolonged severity of pathological sequellae. Whereas calves failing to develop LPS tolerance were identified on the basis of their excessive in vivo plasma TNF- concentrations responses, in vitro TNF- responses of peripheral blood mononuclear cells isolated from each calf and challenged with LPS or PMA did not correlate or predict the magnitude of in vivo plasma TNF response of the calf. Intentional breeding to obtain calves from bulls and/or cows documented as HPR resulted in offspring displaying the HPR character when similarly progeny calves were tested with LPS in vivo with extensive controls in place to account for sources of variability in the general TNF- response to LPS that might compromise interpretation of the data. Feed intake, clinical serology and hematology profiles, and acute phase protein responses of HPR calves following LPS were significantly different from those of calves displaying tolerance. These results suggest that the pattern of plasma TNF- changes that evolve from a low-level double LPS challenge effectively reveal the presence of a genetic potential for animals to display excessive or prolonged pathological response to LPS-related stress and compromised prognosis for recovery.