The MPSII is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), characterized by the accumulation of glycosaminoglycans (GAGs). The major clinical manifestations are joint contractures and often mental retardation. The MPSII has been treated by HSCT/ ERT, but this effectiveness in CNS is limited because of poor uptake of enzyme to cross the BBB. To increase the efficacy of ERT in the brain, we tested intraventricular administration (IVA) procedure of IDS in Ids knockout mice. 20ug of IDS was administered into the ventricle of MPSII mice repeatedly 4 times every 3 weeks. The IDS enzyme activities, GAGs assay and histopathology were measured in mice tissues. The IDS activities were significantly increased in MPSII mice cerebral regions with IVA. In cerebellum, the activities were also elevated to similar levels of normal mice. The accumulation of total GAGs was decreased in the brain treated with IDS. The over expression of Lamp2 was also observed in Purkinje cell of MPSII mice. In MPSII mice tissues with IDS multiple IVAs, the high level IDS activities were maintained and GAGs storage levels were also decreased. These results demonstrate the possibility and efficacy of novel ERT procedure with IVA for MPSII treatment. Conflict of Interest declared. Introduction: MPS II is a X-linked lysosomal storage disorder causing a progressive multisistemic accumulation of glycosaminoglicans (GAGs). Enzimatic replacement therapy (idursulfase) has been introduced in the last years. Case report: We report the case of a 19 years old boy who received diagnosis of MPS II at the age of 4 years by the presence of an occasional heart murmur (R443X mutation). At 14 years he began therapy with idursulfase (dose 0,5 mg/kg/die): urinary GAGs have been decreased significantly. Despite the severe aortic and mitral regurgitation, no heart failure has been detected. The severe bilateral mixed hearing loss and the restrictive respiratory impairment are both stable, while the mild form of obstructive sleep apnea syndrome has been resolved. Hepatomegaly is still present, splenomegaly has been reduced and so the pancytopenia from hypersplenism. A mild thrombocytopenia is still present. Lower limbs muscular trophysm has improved but neither joint stiffness nor bone dysmorphisms did. Mild mental retardation is present. Conclusion: In this patient Idursulfase therapy can be considered effective even if started in adolescence.