CLOVES syndrome is characterized by lipomatous overgrowth associated with vascular malformations, representing a diagnostic and a therapeutic challenge. Rapamycin, an mTOR inhibitor, has proved to be a good therapeutic option in some vascular anomalies. In this article, we report two cases of CLOVES syndrome with good response to oral rapamycin treatment. Objective: To report the outcome of two patients with CLOVES syndrome treated with oral rapamycin. Clinical Cases: Case 1: A three-year-old female preschooler with CLOVES syndrome and history of repeated hospitalizations due to severe infections resulting from macrocystic lymphatic malformations and due to thrombotic episodes. The patient evolved with poor quality of life, multiple hospitalizations, surgical risk and progression of the lesions, therefore, oral rapamycin was indicated. After six months of treatment, clinical and radiological reduction in the size of the lipomatous and lymphatic masses, cutaneous lymphorrhea absence and a significant improvement of her quality of life were observed, without requiring new hospitalizations. Case 2: a ten-year-old female schooler with CLOVES syndrome, who developed scoliosis and deterioration of her motor skills, becoming wheelchair-dependent. Oral rapamycin was indicated, showing improvement in her physical capacity, independence and autonomy, and absence of lymphorrhea after four months of treatment. Conclusion: We propose oral rapamycin for the treatment of patients with CLOVES syndrome who present with complications and deterioration in the quality of life as a result of the disease.