Sphingomyelinosis (spm), an autosomal recessive mutation in mice originally occurred in the C57BL/KsJ inbred strain. Spm/spm mice of this genetic background show striking hepatosplenomegaly with a marked accumulation of sphingomyelin and cholesterol due to a deficiency of sphingomyelinase. However, in spm/spm mice of C57BL/6J and DBA/2J backgrounds, hepatosplenomegaly was not pronounced in spite of marked elevation of hepatic lipid concentrations. The lifespan of C57BL/6J-spm/spm and DBA/2J-spm/spm mice was shorter than that of C57BL/KsJ-spm/spm mice. This appeared to be associated with the comparatively rapid rise in hepatic lipid concentrations, which in turn might be related to the absence of hepatomegaly. Histological study revealed the formation of massive foam cell clusters in the livers and spleens of C57BL/KsJ-spm/spm mice, whereas in the case of C57BL/6J-spm/spm and DBA/2J-spm/spm mice, diffusely scattered foam cells were found. These findings suggest that the functions of reticuloendothelial system (RES) play a crucial role in the development of hepatosplenomegaly in response to lipid accumulation.