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Fatigue and depressive mood are the most significant symptoms experienced by patients with end-stage renal disease. The purpose of this study was to examine the effectiveness of acupressure with massage in fatigue and depression in patients with end-stage renal disease (ESRD) receiving hemodialysis treatment. The study applied an experimental pretest and posttest design. Sixty-two hemodialysis patients participated in the study. Data were collected from two hemodialysis clinics in major hospitals in southern Taiwan. Following consent to the study, subjects were randomly assigned to an acupressure group or a control group. Patients in the acupressure group received acupoint massage for 12 minutes per day, three days per week, for four weeks. Subjects in the control group only received routine unit care. The measures included the Revised Piper Fatigue Scale, and Beck's Depression Inventory. Descriptive statistics, χ2 tests, t-test and analyses of covariance were used for data analysis. The results indicate that subjects experienced a moderate level of fatigue. Nearly 65% of hemodialysis patients had a depressed mood. ANCOVA results indicated that fatigue (F(1,54) = 9.05, p = .004) and depression (F(1,54) = 4.20, p = .045) among patients in the acupressure group showed significantly greater improvement than patients in the control group. The findings of this study provide an interventional model for nurses taking care of ESRD patients.