Zoledronic acid (ZA), an intravenous bisphosphonate, has been widely used for the treatment of osteoporosis. ZA is generally well tolerated, and ZA-related hepatotoxicity is rare. We report a case of hepatotoxicity after ZA infusion in an elderly male patient with primary osteoporosis. The patient had femoral neck and vertebral fractures, and 3 days after ZA 5-mg infusion, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased 23.4- and 15.3-fold, respectively, compared with pre-treatment values. Hepatoprotective agents were administered, and liver enzymes were back to near normal range 9 days later. This case report shows the possible hepatic adverse effects related to ZA infusion. The mechanism of hepatotoxicity caused by ZA is not clear. Acute-phase reaction after ZA infusion may play a role in hepatotoxicity, which should be taken into consideration, especially for the elderly.