Most reports on the effectiveness and side effects of oral versus parenteral calcitriol or alfacalcidol in hemodialysis patients with secondary hyperparathyroidism show no advantage of parenteral treatment. The efficacy and safety of intravenous doxercalciferol (1alphaD(2)) were studied in hemodialysis patients with secondary hyperparathyroidism (plasma intact parathyroid hormone [iPTH]: range, 266 to 3,644 pg/mL; median, 707 pg/mL). These results were compared with those of a previous trial using intermittent oral 1alphaD(2); the same 70 patients were entered onto both trials, and 64 patients completed both trials per protocol. Twelve weeks of open-label treatment in both trials were preceded by identical 8-week washout periods. Degrees of iPTH suppression from baseline were similar in the two trials, with iPTH level reductions less than 50% in 89% and 78% of patients during oral and intravenous treatment, respectively. Grouping patients according to entry iPTH levels (<750 and >/=750 pg/mL) showed similar but more rapid iPTH suppression in the low-iPTH groups, whereas longer treatment and larger doses were required by the high-iPTH groups. Highest serum calcium levels averaged 9.82 +/- 0.14 and 9.67 +/- 0.11 mg/dL during oral and intravenous 1alphaD(2) treatment, respectively (P: = not significant [NS]). Prevalences of serum calcium levels greater than 11.2 mg/dL during oral and intravenous treatment were 3.62% and 0.86% of calcium measurements, respectively (P: < 0.001). Highest serum phosphorus levels during oral and intravenous treatment averaged 5.82 +/- 0.21 and 5.60 +/- 0.21 mg/dL, respectively (P: = NS). The percentage of increments in serum phosphorus levels during oral treatment exceeded that during intravenous treatment during 5 of 12 treatment weeks. Thus, intermittent oral and intravenous therapy with 1alphaD(2) reduced iPTH levels effectively and similarly, hypercalcemia was less frequent, and serum phosphorus levels increased less during intravenous than oral 1alphaD(2) therapy, suggesting that intravenous 1alphaD(2) therapy may be advantageous in patients prone to hypercalcemia or hyperphosphatemia.