MRSA causes a wide diversity of diseases, ranging from benign skin infections to life-threatening diseases, such as sepsis. However, there have been few reports of the pathophysiology and mechanisms of sepsis resulting from the gut-derived origin of MRSA. Therefore, we established a murine model of gut-derived sepsis with MRSA and factors of MRSA sepsis that cause deterioration. We separated mice into four groups according to antibiotic treatment as follows: (i) ABPC 40 mg/kg; (ii) CAZ 80 mg/kg; (iii) CAZ 80 mg/kg + endotoxin 10 microg/mouse; and (iv) saline-treated control groups. Gut-derived sepsis was induced by i.p. injection of cyclophosphamide after colonization of MRSA strain 334 in the intestine. After the induction of sepsis, significantly more CAZ-treated mice survived compared with ABPC-treated and control groups. MRSA were detected in the blood and liver among all groups. Endotoxin levels were significantly lower in the CAZ-treated group compared to other groups. Inflammatory cytokine levels in the serum were lower in the CAZ-treated group compared to other groups. Fecal culture showed a lower level of colonization of E. coli in the CAZ-treated group compared to other groups. In conclusion, we found that CAZ-treatment ameliorates infection and suppresses endotoxin level by the elimination of E. coli from the intestinal tract of mice. However, giving endotoxin in the CAZ-treated group increased mortality to almost the same level as in the ABPC-treated group. These results suggest endotoxin released from resident E. coli in the intestine is involved in clinical deterioration resulting from gut-derived MRSA sepsis.