ObjectiveTo explore the relationship between programmed death-1 (PD-1) inhibitors and cancer-related fatigue (CRF) in patients with malignant melanoma, and to identify associated influencing factors.MethodsA total of 100 patients with malignant melanoma treated at Jinan People's Hospital between April 2019 and April 2024 were included as study subjects. The Chinese version of the Piper Fatigue Scale was used to evaluate patients' fatigue levels within three months before and after the initiation of PD-1 inhibitor therapy.ResultsThere was a significant difference in CRF score before and after PD-1 inhibitor treatment (P < 0.001). Univariate analysis showed no significant association between fatigue severity and factors such as gender, smoking history, tumor site, or PD-1 inhibitor type (all P > 0.05). However, age, tumor stage, anemia, leukopenia, secondary hypothyroidism, secondary adrenal insufficiency (AI), and secondary adrenocorticotropic hormone deficiency (P < 0.05 or P < 0.01 or P < 0.001) were significantly associated with CRF. Multivariate regression analysis identified secondary hypothyroidism, secondary AI, anemia, and leukopenia as independent risk factors for severe CRF in patients with malignant melanoma (all P < 0.05).ConclusionAdverse reactions of PD-1 inhibitors, including secondary hypothyroidism, secondary AI, anemia, and leukopenia, are independent risk factors for CRF in patients with malignant melanoma.