Background: Fatigue is one of the most common adverse effects associated with cancer immunotherapy using checkpoint inhibitors (CPIs). Because treatment-related fatigue also frequently occurs in patients treated with non-immunological therapies, our study aimed to compare the incidence of fatigue in CPI-treated patients with that associated with non-immune therapies in randomised trials. Methods: PubMed and ClinicalTrials.gov were searched for phase III studies using a CPI alone or in combination with chemotherapy or non-immunologic targeted therapy in the experimental arm and control arm using inactive therapies such as placebo or observation, chemotherapy, or non-immunologic targeted therapy. Adverse events listed in the full texts as well as those available from clinicaltrials.gov were reviewed for all identified studies. Results: A total of 60 studies involving 41 435 patients were included in the analysis. All-grade fatigue was reported in 30.4% of patients [95% confidence interval (CI) 29.9% to 31.0%] in the immunotherapy arms of the analysed studies. Using anti-programmed cell death protein 1 agents as reference, the odds ratio (OR) for fatigue was significantly higher both for anti-cytotoxic T lymphocyte-associated antigen 4 agents (OR 1.46, 95% CI 1.04-2.04) and the combination of anti-cytotoxic T lymphocyte-associated antigen 4 and anti-programmed cell death protein agents (OR 1.43, 95% CI 1.12-1.83). Fatigue was significantly less likely to occur in patients treated with CPI compared with patients receiving chemotherapy (OR 0.79, 95% CI 0.73-0.85), but significantly was more common in patients receiving the combination of CPI/chemotherapy compared with patients receiving chemotherapy alone (OR 1.12, 95% CI 1.03-1.22). Conclusions: Although immunotherapy using CPIs was associated with treatment-related fatigue, the occurrence of allgrade fatigue was significantly higher in patients treated with chemotherapy compared with patients receiving CPIs. The risk of fatigue was higher for CPI/chemotherapy combinations than for chemotherapy alone. These results suggest that although the effects of CPIs and chemotherapy are additive, chemotherapy was the dominant cause of treatment-related fatigue in the analysed trials.