Breast cancer is still the leading cause of cancer-related deaths among women aged 20-59 and metastatic breast cancer remains an incurable disease. The therapeutic paradigm of patients with HR-positive HER2-negative metastatic breast cancer has been expanded by the introduction of the inhibitors of cyclin-dependent kinases 4/6. Three compounds, palbociclib, ribociclib, and abemaciclib, have already been approved by the Food and Drug Administration (FDA) for use together with endocrine therapy; abemaciclib is also approved as a single agent. In the first-line setting, all three agents - together with an aromatase inhibitor (AI) - substantially prolonged progression-free survival. Hematologic toxicities are the most common adverse events associated with CDK4/6i, mainly with palbociclib and ribociclib. Due to the hematologic toxicity, the prescribing information of palbociclib (P) recommends monitoring complete blood counts before starting therapy and at the beginning of each cycle, as well as on day 15 of the first 2 cycles. However, there are no guidelines regarding the management of patients candidate to CDK4/6i who have bone marrow impairment. Neutropenia frequently occurs during the treatment with P, whereas thrombocytopenia represents a rare event. We here report a case of a 60-year-old woman with idiopathic thrombocytopenia treated with P plus letrozole, who presented a metabolic complete response.