Pruritus is a common complaint in patients undergoing maintenance hemodialysis. The pathophysiology of pruritus in these patients is not well known, but the role of histamine release from mast cells has been reported. According to the inhibitory effects of zinc on histamine release and reported low levels of serum zinc in hemodialysis patients, we aimed to evaluate the effects of zinc sulfate for the relief of pruritus in these patients. This double-blind, randomized, placebo-controlled trial was conducted on 40 adults with end stage renal disease (ESRD) who were on maintenance hemodialysis in two university hospitals in Isfahan, Iran. Patients were randomized to receive either zinc sulfate (440 mg/day) or placebo for two consecutive months. Pruritus was assessed at baseline and then every two weeks using a numerical rating scale from 0 to 10 until one month after treatment. Drug side effects were also assessed along with pruritus. There were 40 patients with a mean age of 55.5 ± 15.2 (72.5% male) who completed the study. The two groups were similar in baseline characteristics. Pruritus was decreased in both groups after treatment but there was a significantly greater decrease in the zinc sulfate group compared with placebo (P = 0.018). Patient compliance was good and no severe side effects were observed. Zinc sulfate (440 mg/day) is more effective than placebo for the relief of pruritus in patients under maintenance hemodialysis. Further studies with larger sample size, longer treatment duration and follow-up and with various dosages of zinc sulfate are recommended.