Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease resulting from deficiency of the lysosomal enzyme α‐L‐iduronidase. A murine model which shows complete deficiency in α‐L‐iduronidase activity has been developed and shows phenotypic features similar to severe MPS I in humans. Here we report on the long‐term clinical, biochemical, and pathological course of MPS I in mice with emphasis on the skeletal and central nervous system (CNS) manifestations. Affected mice show a progressive clinical course with the development of coarse features, altered growth characteristics and a shortened life span. Progressive lysosomal accumulation is seen in all tissues. Skeletal manifestations represent the earliest clinical finding in MPS I mice with histologic analysis of growth plate and cortical bone revealing evidence that significant early pathology is present. Analysis of the CNS has revealed the novel finding of progressive neuronal loss within the cerebellum. In addition, brain tissue from MPS I mice shows increased levels of GM₂ and GM₃ gangliosides. This murine model clearly shows phenotypic and pathologic features which mimic those seen in severe human MPS I and should be an invaluable tool for the study of the pathogenesis of generalized storage disorders.