The Fmr1 gene knockout mouse is a model for the human Fragile X mental retardation syndrome. Fmr1 knockout mice with a C57BL/6-129/OlaHsd hybrid background have been reported to have only a very mild deficiency in learning the Morris water maze task. We compared the effect of this knockout mutation on learning in mice with either an FVB/N-129/OlaHsd hybrid background or a C57BL/6 background. When FVB-129 mice were tested in a cross-shaped water maze task, the knockout mice showed a pronounced deficiency in their ability to learn the position of a hidden escape platform in comparison to normal littermates. In contrast, knockout mice with a C57BL/6 background learned the maze just as well as their normal littermates. Fear conditioning did not reveal differences between knockout and normal mice in either background. These results show that silencing the Fmr1 gene clearly interfered with learning a specific visuospatial task in FVB/N-129 hybrid mice but not in C57BL/6 mice. The strain dependence may model the influence of genetic background in the human Fragile X syndrome.