The paper reports the case of a three-month-old girl presenting with maculopapular lesions all over her scalp, trunk, axilla region and groin. One month earlier she had been diagnosed with LCH through skin biopsy for persisting maculopapular rash. No other organs appeared to be involved: blood and urine tests, chest X-rays and abdominal ultrasound were normal. On physical examination, the child’s general conditions were poor and she was pale and dyspneic. Massive cervical lymphadenopathy and hepatosplenomegaly were diagnosed. Laboratory tests showed anaemia and thrombocytopenia, coagulopathy and hypoalbuminemia while chest X-rays revealed a mediastinal mass. Multisystem LCH with risk organs involvement (liver, spleen, bone marrow) was diagnosed. Despite the initial good response, the disease relapsed following first and second-line chemotherapy. Due to the evidence of B-RAF^V600E mutation, targeted therapy with vemurafenib was introduced with excellent response. This case highlights the importance of surveillance in skin-limited neonatal LCH due to the risk of rapid evolution into an aggressive and refractory multisystem disease.