Introduction: Zoledronic acid (ZA), a bisphosphonate, increases the levels of cytolcines, such as interleuldn-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), and reactive oxygen species (ROS) in subjects without cancer. Increased production of ROS, TNF-alpha, and IL-6 during ischemia and reperfusion (I/R) injury stimulates apoptosis that leads to renal injury. We aimed to investigate whether ZA treatment has a protective effect on renal tissues during I/R. Materials and Methods: Twenty-four Sprague-Dawley rats were used in this study, and they were subdivided randomly into three groups, each containing eight rats. Infrarenal abdominal aortic cross ligation was performed on the I/R group. After 2 h of ischemia, 2 h of reperfusion was applied. A single dose of 100 mu g/kg ZA was administered intraperitoneally to the ZA group. I/R was performed after 48 h. Results: Whereas TNF-alpha, IL-6, and nitric oxide (NO) levels of the I/R group were higher than those of the control group, TNF-a, IL-6, and NO levels of the ZA group were higher than those of the I/R group [TNF-alpha (p=0.038), IL-6 (p=0.012), NO (p=0.002), and caspase-3 (p=0.037)] and the control group [TNF-alpha (p<0.001), 11-6 (p<0.001), NO (p<0.001), and caspase-3 (p<0.001)]. Whereas the carbonic anhydrase II (CA-II) level of the ZA group was lower than that of the control group (p=0.040), the CA-II level of the I/R group was higher than that of the control group (p=0.020). Conclusion: ZA may aggravate renal injury during I/R by increasing cytokine production and apoptosis. It may also increase renal injury and metabolic acidosis during PR by suppressing CA-II enzyme activities.