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Project The aim of this study was to determine the effects of zinc supplementation on serum zinc and leptin levels as well as on anthropometric status and some biochemical parameters in hemodialysis (HD) patients. Procedure In this randomized, double-blind, and placebo-controlled trial, sixty HD patients were randomly divided into groups to receive a daily supplement of 100 mg elemental Zn (supplemented group) or placebo (control group) for 60 days. Anthropometric measurements were taken using standard calibrated instruments. Serum zinc and leptin levels were determined by atomic absorption and ELISA method respectively before and after intervention. Results Zinc supplementation resulted in significant increase in the mean serum zinc level in the experimental group while changes observed in the placebo group were not significant. The mean serum leptin in women part of the experimental group was decreased significantly after supplementation. After adjusting for age, BMI, body fat (%), serum zinc and dietary Zn intake, a negative and significant association was observed between serum zinc and leptin levels in all subjects (β = −0.33, P = 0.03) as a result of Zn supplementation. Conclusions More studies are needed to clarify the mechanisms by which serum leptin level is influenced as a result of zinc supplementation in HD patients.