This study examined the effect of sepsis following trauma in a reproducible model of sepsis-cecal ligation and puncture (CLP)-in endotoxin-sensitive (C3H/HeN) and endotoxin-resistant (CeH/HeJ) mice. Studies used CLP with a 25-gauge needle at different time intervals following injury, as induced by femur fracture (FF), to determine the effects of sublethal sepsis on survival after trauma. There was a 3% mortality for FF alone in both groups. Mortality in C3H/HeJ mice was not significantly increased over FF alone except when CLP followed FF by 3 days (45%, P < 0.02, Chisquare). In contrast, C3H/HeN mice had significantly increased mortality rates (75 to 90%, P < 0.001) versus FF alone at all intervals between FF and CLP. Mortality for FF plus CLP was significantly greater for C3H/HeN compared to C3H/HeJ (P < 0.001) for all time intervals between FF and CLP. In conclusion, animals exposed to a septic episode following FF had significantly greater mortality than FF animals without a septic challenge. Endotoxin-sensitive mice had significantly higher mortality after CLP and significantly increased mortality when CLP followed FF (regardless of timing) compared to endotoxin-resistant mice. © 1991.