Background: Despite the high frequency of cancer related fatigue (CRF) in patients with advanced cancer (PAdC), there are no effective pharmacological treatments. Our group previously found that the placebo response was 56% among PAdC participating in CRF trials. There are no clinical trials using open label placebo for CRF in PAdC. The purpose of this study was to determine the effects of open labeled placebo (OLP) compared to waitlist control (WLC) in reducing CRF in PAdC using Functional Assessment of Chronic Illness Therapy-Fatigue subscale (FACIT-F). Methods: In this randomized controlled trial, PAdC with fatigue ≥ 4/10 on ESAS were randomized to OLP one tablet twice a day or WLC for seven days (primary end point). After week 1 in patients of both arms received placebo for 3 weeks. Changes in FACIT-F from baseline to Day 8 (primary outcome), and changes after 21 days of placebo in both arms were assessed. Secondary outcomes included quality of life (QOL)[FACT-G], fatigue dimensions(MFSI-SF), depression(CES-D), and Fatigue cluster(ESAS fatigue, pain, and depression). Results: 82/90(91%) patients were evaluable. The adherence to placebo [mean%(SD)], was 93.6(18.6), and 88.1(20.2) at Day 8 and Day 29 respectively in OLP arm, and 89.9 (73) at Day 29 in WLC arm. The mean(SD) FACIT-F change at day 8 was 6.6 (7.6) after OLP, 2.1 (9.4) after WLC (p = 0.016). On days 15 and 29, when all patients received OLP, there was significant improvement of CRF but not difference between arms. FACT-G Total Score, FACT-G EWB, ESAS Fatigue, and Fatigue cluster score, all showed significant evidence of reduced CRF in the OLP arm on Day 8 of the study (p = 0.002, 0.030, 0.029, and 0.044, respectively). There was no significant difference in adverse events between the two groups. Conclusions: Open labeled placebo was efficacious in reducing CRF, fatigue cluster, and QOL in fatigued advanced cancer patients at the end of one week. The improvement in fatigue was maintained for 4 weeks. Further studies of this intervention are justified. Clinical trial information: NCT03927885.