Bisphosphonates represent potent antiresorptive drugs that are established for therapy of patients with benign and malignant bone diseases. Zoledronic acid is an iv aminobisphosphonate that is administered annually against osteoporosis. Because of its potency and the parenteral route of administration, zoledronic acid is an alternative to oral bisphosphonates, in particular in elderly patients with multiple comorbidities. The most common side effects include an acute-phase reaction and mild and transient hypocalcemia. Here, we report three cases of seizures that developed after the administration of zoledronic acid. We review case histories and laboratory results of three patients with seizures associated with the administration of zoledronic acid. We discuss their course and comorbidities in the context of the published literature. All three patients were elderly persons with multiple comorbidities, including neurological diseases, that required parenteral bisphosphonates for severe osteoporosis with concurrent contraindications for oral bisphosphonates. We analyze potential mechanisms underlying these seizures in association with zoledronic acid exposure and discuss potential strategies to minimize this risk.