Purpose: This study aimed to evaluate the effect of illness perception on depression and quality of life in patients with hemodialysis. Methods: This is a cross-sectional study using structural equation modeling. Depression, quality of life and cognitive and emotional illness perceptions were measured by the Center for Epidemiologic Studies Depression-10 (CESD-10), Short Form-36 version 2 (SF-36v2), and Brief Illness Perception Questionnaire (BIPQ) in 272 hemodialysis patients. Results: Prevalence of depression was 76.1%, and higher in female patients on hemodialysis. Cognitive illness perception had effect on depression and quality of life, while emotional illness perception had effect only on depression. Quality of life was explained 69.6% through depression (β=-.74, t=-8.17) and cognitive illness perceptions (β=.21, t=3.06), while depression was explained 40.5% through cognitive (β=-.34, t=-5.99) and emotional(β=.59, t=9.37) illness perceptions. Conclusion: In the inevitable choice of dialysis, illness perception could decrease depression and improve quality of life in hemodialysis patients.