BACKGROUND: GWAS can identify targets of marketed drugs that are strongly associated with disease(s) different from approved indication, providing opportunities to substantially shorten the drug development process by repositioning the drug as treatment for the newly identified disease, potentially yielding substantial socioeconomic benefits. OBJECTIVES: To estimate economic benefits of repositioning three drugs to GWAS-identified diseases METHODS: GWAS were used to identify denosumab (currently for osteoporosis) as possible treatment for Crohn’s disease, melatonin (circadian adjustment) for diabetes, and niacin (lipid-lowering) for aortic stenosis (AS). Economic models were constructed for the three illnesses--using data from Canadian registries, claims databases and clinical trials--comparing current management of the target illness with use of the repositioned drug. Costs (2013 CAD) were obtained from Medicare, Ontario Case Costing Project and price lists. Analyses covered each province and Canada. RESULTS: In all three cases, the repositioned product was dominant over current treatment mix, even at relatively low levels of uptake (>5%). With 50% uptake, in Crohn’s, denosumab would provide substantial reductions in side-effects and savings of $1,619/pt, resulting in $161 million in annual savings across Canada; in diabetes, melatonin would save $205/pt annually, or more than $365 million for Canada, assuming equal efficacy; in AS, niacin would save $4.5 million in Quebec alone, largely by averting valve replacement surgery, providing additional benefits via reduced associated morbidity and mortality. Extensive sensitivity analyses showed these results to remain directionally the same except at extremely low rates of uptake or with significant increases in the price of the repositioned product. CONCLUSIONS: Using GWAS data to reposition existing drugs to other diseases offers sizeable reductions in the cost and time of drug development and would provide considerable economic benefits to the health care system. Additional efforts should be made to pursue this attractive path to effective “novel” treatments