Introduction: Increased serum levels of bone-resorptive cytokines such as interleukin-1β (IL-1β) and interleukin-6 (IL-6) have been implicated for changes in bone remodeling in hemodialysis patients. In this prospective randomized study, we aimed to compare the effect of oral and intravenous (IV) pulse calcitriol on serum levels of IL-1β and IL-6. Patients and Methods: Twenty-eight hemodialysis patients were included and consecutively randomized to receive either oral (n = 14, M/F = 7/7, mean age 42 ± 15 years) or IV pulse (n = 14, M/F = 6/8, mean age 38 ± 14 years) calcitriol treatment. No difference was found between groups for age, sex distribution, primary renal disease, mean time on hemodialysis and baseline biochemical parameters including serum levels of IL-1β and IL-6. Results: The percent fall of intact parathyroid hormone (iPTH) was significantly less with oral compared to IV calcitriol between 0 and the 3rd month (32 ± 21 vs. 56 ± 28%, p = 0.03). However, the percent fall in iPTH at the 6th month of the therapy was not different in the oral group compared to the IV group (57 ± 22 vs. 73 ± 24%, p = 0.12). The increase in bone mineral densities was higher in the IV group than the oral group. Oral and IV calcitriol caused a significant fall in IL-1β (p = 0.02 and p = 0.03, respectively) and IL-6 levels (p = 0.02 and p < 0.001, respectively) at the 6th month of treatment. The percent fall in serum IL-6 levels at the 6th month was significantly greater in the IV compared to the oral group (61 ± 18 vs. 36 ± 33%, p = 0.04), while the percent changes in serum IL-1β levels were similar. Conclusion: IV calcitriol therapy has a greater suppression of PTH at the 3rd month of the therapy. Despite no difference in serum PTH levels at the 6th month, IV therapy has a greater increase in bone mineral densities and a greater decrease in serum IL-6 levels. These findings suggest IV calcitriol treatment has a superior effect on bone remodeling by influencing the levels of bone-resorptive cytokines as compared to the oral therapy group, beyond its suppressive effect on iPTH.