Zoledronic acid is one of the most commonly used intravenous, highly potent amino diphosphonate salts worldwide and is commonly used in patients with primary or secondary osteoporosis, most of whom are well tolerated. There are currently no reports of severe sepsis induced by zoledronic acid. Here we present the first case of severe sepsis induced by zoledronic acid. We reviewed the literature and found that there is currently a lack of reports on severe sepsis induced by zoledronic acid or other diphosphonates. A 58-year-old woman with severe osteoporosis and Behcet disease developed severe sepsis after treatment with zoledronic acid. Sepsis, septic shock, acute kidney injury, intestinal infection, Behcet disease. The patient was given intensive care immediately after admission, and massive fluid infusion to expand blood volume could not maintain normal blood pressure. Metaraminol was added to maintain circulatory stability, piperacillin-tazobactam was used to strengthen anti-infection, and glucocorticoids were used for anti-inflammatory treatment. The patient was discharged with improvement and followed up in the outpatient clinic. The inducing mechanism of zoledronic acid is not clear, but when the patient has immunosuppression, the use of zoledronic acid should be cautious and monitored. In conclusion, severe sepsis induced by zoledronic acid is a rare but serious complication, and physicians should be aware of this adverse event in time to avoid serious consequences.