Purpose <p>This review assesses the efficacy of Open Label Placebos (OLPs) for the treatment of Cancer Related Fatigue (CRF) and the methodological challenges of such trials.</p> Methods <p>We included randomized controlled trials comparing OLPs to treatment as usual or waitlisted controls in adults (≥ 18&#xa0;years) with moderate CRF. Eligible participants included cancer survivors and advanced cancer patients. We searched PubMed, MEDLINE, and Cochrane databases on July 12, 2025. Risk of bias (ROB) was assessed using the Cochrane ROB2 tool. Results were synthesized narratively due to heterogeneity. Quality of evidence was assessed for the use of OLPs for the treatment of CRF in cancer survivors using the GRADE approach.</p> Results <p>Three RCTs (total <i>N</i> = 87) met inclusion criteria, two studied the changes in cancer survivors, one studied advanced cancer patients. All trials had high ROB, particularly due to the lack of blinding of assessors (patients) and the use of patient-reported outcomes. All studies reported CRF improvement in the OLP arms. Two showed significant reductions in fatigue compared to controls. The quality of evidence was found to be very low.</p> Conclusion <p>Though an overall positive effect is seen, the evidence supporting OLPs for CRF is of very low quality. This is mostly due to methodological challenges seen in trials using patient-reported outcomes where the participants can discern their allocation. Larger, methodologically robust studies are needed to clarify OLP efficacy. Functional fatigue scales, in place of patient-reported outcomes, may reduce bias in future trials.</p> Registration <p>PROSPERO CRD42024449166.</p>