Introduction: Despite the high prevalence of restless legs syndrome (RLS) in hemodialysis patients, few studies have investigated the effect of pramipexole and gabapentin on the severity of RLS in these patients. Objectives: The study aimed to evaluate the effects of pramipexole and gabapentin on the treatment of RLS in end-stage chronic renal failure patients undergoing hemodialysis. Patients and Methods: Using the diagnostic criteria the presence of RLS was investigated in all hemodialysis patients admitted to the dialysis ward of Bu Ali Sina and Velayat hospitals in Qazvin, Iran. Out of 162 patients, 96 patients had RLS and 60 patients with moderate to severe RLS were enrolled in the study. The selected patients were randomly divided into two groups including pramipexole (0.18 mg daily) and gabapentin (100 mg daily). The two groups were treated for 4 weeks. Results: The prevalence of RLS was 59% (96 out of 162 patients). After the intervention, the severity of RLS was significantly decreased in all patients and also in each of the pramipexole and gabapentin groups (P<0.001). Moreover, after the intervention, the rate of improvement in RLS severity in the pramipexole group (16.8 ± 6.5) was significantly higher than that in the gabapentin group (13.0 ± 7.3; P=0.036). Conclusion: The findings of the study showed that the severity of RLS in hemodialysis patients undergoing 4 weeks of treatment with pramipexole or gabapentin was significantly reduced; in addition, the rate of improvement in RLS severity was higher in pramipexole group.