Persistent cancer-related fatigue (PCRF) is a symptom experienced by many cancer survivors. Acupressure offers a potential treatment for PCRF. We investigated if acupressure treatments with opposing actions would result in differential effects on fatigue and examined the effect of different "doses" of acupressure on fatigue. We performed a trial of acupressure in cancer survivors experiencing moderate to severe PCRF. Participants were randomized to one of three treatment groups: relaxation acupressure (RA), high-dose stimulatory acupressure (HIS), and low-dose stimulatory acupressure (LIS). Participants performed acupressure for 12-weeks. Change in fatigue as measured by the Brief Fatigue Inventory (BFI) was our primary outcome. Secondary outcomes were assessment of blinding and compliance to treatment. Fatigue was significantly reduced across all treatment groups (mean ± SD reduction in BFI: RA 4.0 ± 1.5, HIS 2.2 ± 1.6, LIS 2.7 ± 2.2), with significantly greater reductions in the RA group. In an adjusted analysis, RA resulted in significantly less fatigue after controlling for age, cancer type, cancer stage, and cancer treatments. Self-administered RA caused greater reductions in fatigue compared to either HIS or LIS. The magnitude of the reduction in fatigue was clinically relevant and could represent a viable alternative for cancer survivors with PCRF.