CONTEXT: Annual infusions of zoledronic acid 5 mg over 3 years have been shown to reduce fracture incidence. There is now evidence that the effects of a single dose of zoledronic acid on bone mineral density and bone turnover last for much more than a year. Whether this is associated with sustained fracture prevention is not known. OBJECTIVE: The objective of the study was to assess fracture incidence after only 1 infusion of zoledronic acid. DESIGN: The design of the study included post hoc analysis of subgroups of subjects from 2 trials, who received only 1 study infusion. SETTING: The study included multicenter, randomized controlled trials. PARTICIPANTS: A total of 1367 subjects from HORIZON-PFT and HORIZON-RFT studies who received only 1 of the planned annual infusions participated in the study. INTERVENTION: The intervention of the study consisted of 1 infusion of zoledronic acid or placebo. MAIN OUTCOME MEASURE: Clinical fracture was the main outcome measure of the study. RESULTS: Mean follow-up period was 1.5 years. In patients who received only a single infusion, there was a 32% reduction in clinical fracture comparing zoledronic acid with placebo over 3 years of follow-up (95% confidence interval 2-53%, P = .04), comparable with the fracture reduction seen in those who had 3 or more annual infusions (34%; 95% confidence interval, 23-43%, P < .0001). New morphometric vertebral fractures were reduced by 68% in the single-infusion group (P = .004). The between-group differences in total hip bone mineral density at 3 years were 3.8% in those receiving 1 infusion and 6.2% in those receiving 3 infusions. CONCLUSIONS: In this post hoc analysis based on postrandomization subgroups, fracture risk appears to be reduced for more than 1 year after a single infusion of zoledronic acid. Prospective studies designed to assess this possibility are now warranted.