PURPOSE: To evaluate the impact of the type of CDK4/6 inhibitor administered and comorbidities on the quality of life in patients with metastatic breast cancer, as well as the correlation between quality of life and patient outcomes. MATERIALS AND METHODS: This prospective single-center study utilized four internationally validated questionnaires: the EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Core Cancer Quality of Life Questionnaire), the Depression, Anxiety, and Stress Scale-21 (DASS-21), the Multidimensional Fatigue Inventory (MFI), and the Pittsburgh Sleep Quality Index (PSQI), administered to a cohort of 76 patients undergoing treatment for metastatic breast cancer with CDK4/6 inhibitors. RESULTS: Ribociclib is associated with fewer insomnia problems and appears to provide better sleep quality compared to other CDK4/6 inhibitors. Mental fatigue and loss of appetite negatively influence patient survival. Patients with comorbidities reported more severe insomnia and constipation. Comorbidities are associated with a lower quality of life, reflected in greater fatigue, insomnia, and constipation, as well as increased scores for depression and stress. CONCLUSIONS: Assessing global quality of life in metastatic breast cancer patients is essential, as it can predict patient progression and should be integrated into every breast cancer unit.