Background and Aim. Depression is the most common psychological disorder in hemodialysis patients which decreases their quality of life and increases the mortality. This study was conducted to assess the effect of regular exercise on depression in hemodialysis patients. Methods. In a randomized clinical trial, 51 hemodialysis patients were allocated in two groups. Beck Depression Inventory (BDI) scale was used to assessing depression rate in participants. Designed program was educated using poster and face-to-face methods for case group. Intervention was carried out three times a week for ten weeks. At the beginning and the end of the study, depression rate of the subjects was assessed. Data was analyzed by SPSS16 software and descriptive and inferential statistics. Findings. According to the results of this study, there were no differences between case and control groups in depression rate at the beginning of the study, but there was significant difference after intervention (P = 0.016). In the beginning of the study, the mean and SD of depression in case group were 23.8 ± 9.29 and reduced to 11.07 ± 12.64 at the end (P < 0.001). Conclusion. The regular exercise program could reduce the depression in hemodialysis patients; therefore it is suggested for training this program for hemodialysis patients. This trial is registered with Iranian Registry of Clinical Trial (IRCT) number IRCT201205159763N1.