The use of oral bisphosphonates in the primary care setting is increasing, most commonly to preserve bone density and prevent the development or progression of osteoporosis. We report a case of profound hypocalcemia occurring in a patient who underwent thyroidectomy while receiving chronic oral risedronate therapy for osteoporosis. In addition, the hypocalcemia was refractory to treatment for several days, necessitating a prolonged hospital stay. A review of the literature yielded no similar cases to date. We propose that the frequently observed transient hypocalcemia after thyroidectomy was exacerbated by the alterations in calcium homeostasis produced by bisphosphonate therapy and urge cessation of these agents for several weeks prior to surgery. A review of the relevant literature is provided.