Background: As an important member of organic tin compounds, Trimethyltin (TMT) exists widely in industrial and agricultural productions. TMT can induce significant neurodegeneration in the limbic system, particular in hippocampus. However, the molecular mechanisms in TMT-induced learning and memory impairment are not fully clear. Thus, this research was to explore the role of Synaptophysin (SYP) and Ubiquitin-ligating enzyme Siah-1 in TMT-induced nerve impairment and the protective effect of hydrogen rich water (HRW). Methods: Male BALB/c mice were randomly divided into 4 groups: control group (saline, 4 ml/d, i.p.for seven days), HRW group (4 ml/d, i.p.for seven days) , TMT group (2.25mg/kg, i.p. at the seventh day ), and HRW plus TMT group. The spatial learning and memory was tested by Morris water maze, the protein level of SYP and Siah-1were determined by western blot& immunocytochemical analysis, and the tin contents were detected by ICP-MS. Results: The TMT-treated mice showed significant learning and memory disability. Moreover, TMT increased the level of Siah-1, reduced the expression of SYP in hippocampus and cortex. After 7 days of continuous pretreatment with HRW, the mice showed better memory ability, the expression of Siah-1 and tin content decreased accompanied with the increase of SYP. Conclusions: These results showed that HRW ameliorated the decrease of SYP and the nerve impairment induced by TMT, reduced tin content and up-regulated the expressions of Siah-1, and it might be an important role in the protection of neurodegenerative diseases induced by TMT.