Transgenic mice expressing various combinations of structural and regulatory genes of human foamy virus (HFV) develop a neurodegenerative syndrome. delta gpe transgenic mice (which express the auxiliary bel-1 and bet genes along with truncated forms of gag, pol, and env) develop a severe neurological syndrome consisting mainly of spastic tetraparesis and blindness, and show neuronal loss in the hippocampus and cerebral cortex. In addition, mice in two of eight delta gpe lines developed an ataxic gait. Here we studied the phenotype of these two lines, and show that these mice exhibit progressive degeneration of their cerebellar granule cells beginning at 4-8 weeks of age. Transgenic mRNA and HFV proteins accumulate in cerebellar granule cells immediately before the onset of degeneration. The Purkinje cell layer is largely unaffected by this pathological process. Probably due to the loss of granule cell processes, the cerebellar molecular layer is narrowed in the late stages of the disease. These findings indicate that HFV gene products can be neurotoxic for cerebellar granule cells.