OBJECTIVES: This study seeks to compare the cost-effectiveness of bisphosphonates for the treatment and prevention of post-menopausal osteoporosis (PMO). METHODS: A literature review was conducted to obtain all relevant articles published through the end of 2009 that evaluate the cost-effectiveness of bisphosphonates for the treatment and prevention of PMO. PubMed and the Cochrane Database were used to search for the terms “bisphosphonates” and “cost-effectiveness.”  Articles were limited to those evaluating at least one of the four products with an indication approved by the United States Food and Drug Administration for PMO: alendronate, ibandronate, risedronate, or zoledronic acid. Articles focusing on screening efforts, or evaluating the treatment of men, glucocorticoid-induced osteoporosis, or cancer-related bone complications were excluded. A manual review of the included articles’ references was also performed.   RESULTS: The literature search resulted in 189 articles of which 18 met the criteria for inclusion in this evaluation. Of these 18 studies, many examined the use of more than one bisphosphonate, therefore, the total number of comparisons identified for alendronate, ibandronate, risedronate, and zoledronic acid were 13, 3, 8, and 1, respectively. The incremental cost-effectiveness ratios obtained from this analysis varied greatly for all included agents: alendronate ranged from -$25,296.12 (cost-savings) to $934,883.71; ibandronate from $10,354.68 to $15,023.90; risedronate from $1,468.75 to $241,410.15; and zoledronic acid from $1,791.42 to $2,205.39. These results varied based on the included women’s age and underlying risk factors, the specific costs accounted for in each analysis, and the total duration of treatment. CONCLUSIONS: Bisphosphonates represent cost-effective treatment options for the prevention and treatment of PMO. Given the evidence available, it is difficult to determine whether one agent is conclusively more cost-effective than another for this indication. Further studies directly comparing bisphosphonates should be conducted to evaluate their comparative cost-effectiveness.