Introduction: Depression is the most common psychological problems in hemodialysis patients that may lead to decreased quality of life and increased mortality rate. The aim of this study was to investigate the effect of foot reflexology on depression in patients undergoing hemodialysis. Methods: This clinical trial conducted on 78 patients who were admitted to hemodialysis wards in Imam Ali hospital and Iran Mehr Clinic of Bojnord City. Probability convenient sampling technique was used to select the sample. The patients randomly assigned to three groups including: experimental, control and placebo groups. Beck Depression questionnaire was used to measure the level of depression before and after the intervention. Foot reflexology was done in the experimental group, a simple foot massage without pushing standard reflexology points in placebo group, and the routine care in control group was conducted. Data analysis was done using SPSS 16 and ANOVA. Results: Mean depression score for patients in the experimental group, placebo group and control group were: (P < 0.001), (P = 0.016), and (P = 0.042), respectively. The depression was increased in the intervention and placebo group and had a reduction in the control group. Conclusions: Reflexology is an effective medical intervention in reducing depression in patients undergoing hemodialysis.