It has been reported that inosine has no direct neuroprotection against respiratory inhibitors due to the absence of purine nucleoside phosphorylase in neurons. Recent evidence, however, has shown that inosine has direct neurotrophic effects. Thus, lack of direct neuroprotection, as reported before, may not be a general conclusion, but is related to special types of injury. We used PC12 cells to explore direct neuroprotection of inosine against high concentration of zinc sulfate, an injury different from the previous one and found that inosine reduced the mortality of PC12 cells significantly in a dose dependent manner. The results indicate that inosine can directly protect neurons from zinc-induced injury, and such effect might be mediated via mechanism(s) other than purine nucleoside phosphorylase.