The duration of the antiresorptive effects of the intravenous bisphosphonate, zoledronate, is not known. Recently, we reported that two annual 4-mg doses of zoledronate suppressed bone turnover and increased BMD in HIV-infected men over 24 mo. We set out to determine the persistence of these effects after two doses of zoledronate. Thirty-three HIV-infected men who completed a randomized trial of 4 mg annual zoledronate (n = 17) or placebo (n = 16) were studied for a further 12 mo, during which time no skeletal therapy was administered. Participants received calcium (400 mg/d) and vitamin D supplements (50,000 IU/mo) for the first 24 mo of the study only. Biochemical markers of bone turnover and BMD were measured every 6 mo. Bone turnover markers were stably suppressed at 24 and 36 mo (12 and 24 mo after the second annual dose of zoledronate, respectively). There were no significant within-group changes in urine N-telopeptide, serum C-telopeptide, and osteocalcin between 24 and 36 mo (p > 0.07), and at each time point, each of the turnover markers was significantly lower in the zoledronate group. There were also no significant between-group differences in the changes in BMD at each site between 24 and 36 mo (p > 0.5), and at each time point, BMD at each site was significantly higher in the zoledronate group. These results suggest that the antiresorptive effects of zoledronate last >12 mo and raise the possibility that zoledronate could be administered less frequently than annually. Randomized trials that address this issue should be performed.