Background/Aims: 1,25-Dihydroxyvitamin D<sub>3</sub> (1,25-(OH)<sub>2</sub>D<sub>3</sub>) plays an important role in regulating immunologic responsiveness in addition to its effects on bone metabolism. This is potentially beneficial in the transplant setting. Animal studies have demonstrated the utility of 1,25-(OH)<sub>2</sub>D<sub>3</sub> in prolonging allograft survival. Therefore, we evaluated the effects of 1,25-(OH)<sub>2</sub>D<sub>3</sub> (oral calcitriol) in human renal transplant recipients. Methods: A case-control study was undertaken assessing the effects of calcitriol on transplant function. The effect of calcitriol on renal function was analyzed using general linear mixed modeling of the change in slope of serum creatinine (Scr) prior to and following the start of calcitriol therapy. Results: There was a significant increase in baseline Scr (p < 0.001) prior to starting calcitriol. Following initiation of calcitriol, there was a deceleration in the rate of loss of graft function (p = 0.031 at day 300 of therapy). Graft survival was also prolonged in calcitriol-treated patients compared to a control population with evidence of chronic allograft nephropathy but no calcitriol therapy (p < 0.03). Overall, there were no adverse or harmful effects related to calcitriol therapy. 1,25-(OH)<sub>2</sub>D<sub>3</sub> therapy was associated with (1) a deceleration in the rate of loss of renal function in transplant recipients with more than one year of allograft function, and (2) no significant change in allograft function early after transplantation. Conclusion: These data suggest that short- and long-term prospective trials evaluating 1,25-(OH)<sub>2</sub>D<sub>3</sub> or 1,25-(OH)<sub>2</sub>D<sub>3</sub> analogs in human kidney transplantation are warranted. Such trials may help us elucidate mechanism and duration of action, as well as safety issues related to these novel immunomodulatory agents.