Introduction: Rectal cancer is a heterozygous disease in which cancerous cells grow in the rectum and lower parts of the colon. The primary cause of this cancer is not yet known, but factors such as over age ۵۰, smoking, family history, improper diet or having a history of polyps and inflammatory bowel disease are the major risk factors for developing the rectum cancer. The rectum cancer symptoms are mainly characterized by rectal bleeding, but clinical signs such as fatigue, shortness of breath, anemia, bowel obstruction, weight loss, and dizziness may also be observed. Radiotherapy, chemotherapy, and surgery are the most common therapeutic approaches of rectal cancer. Almost all of the given therapies, such as radiotherapy could cause a declination in blood counts which could result in hematological disorders. Recent studies have demonstrated that administration of melatonin could reduce the adverse effects of radiation through activating and enhancement of the cellular anti- oxidant system in many animal models. In this study, we aimed to examine the radioprotective effects of melatonin on the blood cell counts of patients with rectum cancer undergoing radiotherapy. Method and Material: This double-blind placebo-controlled study conducted on ۶۰ rectal cancer patient referred to Rajaii Hospital of Babolsar, Iran. An equal number of patients were randomly assigned to the control group which received placebo and study group which received ۲۰ mg melatonin a day as an intervention. The capsules of ۲۰ mg melatonin were administered once a day for five days a week until ۲۸ days at ۴۵ minutes before radiotherapy, orally at ۱۱ AM for ۲۸ days. Blood samples were taken before melatonin receiving at day ۱ and also day ۲۸, then, to measure the changes in blood cell counts representing our primary outcomes, the samples were analyzed by Sysmex K۸۱۰i auto- analyzer. Result: The blood cells counted in both groups before and after administration of melatonin and placebo. The number of male and females was ۲۰ and ۱۰ respectively for both groups. The mean ages of participants were ۵۳.۵۸± ۷.۴۱. the blood cells count changes have been compared before and after receiving melatonin or the placebo. Our results showed that the platelet, white blood cells, lymphocyte and neutrophil population reduction induced by radiotherapy were slighter or even insignificant in melatonin recipients compared to control. However, the difference between red blood cells in both groups was not significant. Conclusion: This study is the first in vivo study in patients with rectal cancer that has been used melatonin as a radio-protector to reduce the harmful effects of treatment. Our results are indicating that melatonin could prevent or minimize the unfavorable effects of radiotherapy on blood cell count reductions by attenuating the adverse influence of radiation, probably through stimulation of cellular anti-oxidant potential as previously reported in animal models.