Cell division at the end of mitosis and G1 is controlled by Cdh1, an activator of the E3-ubiquitin ligase anaphase-promoting complex (APC) that promotes the ubiquitylation and degradation of mitotic cyclins and other substrates (1). The finding that Cdh1-APC is active in post-mitotic neurons (2) has raised the interest in the role of cell cycle proteins in neurodegenerative diseases. Recently, we reported that Cdh1 silencing, using a small hairpin RNA (shRNA) strategy, triggered cyclin B1 accumulation that preceded apoptotic death in post-mitotic neurons (3). Though these results pointed out the essential role of Cdh1 for neuronal survival, it remained elusive whether Cdh1 would directly promote cellular protection in relevant neurodegenerative paradigms. Thus, here we aimed to investigate the role of Cdh1 at dictating neuronal vulnerability in excitotoxic damage, i.e. a common hallmark in several neurodegenerative disorders. To achieve this, rat cortical neurons in primary culture were incubated with glutamate (100 µM plus 10 µM glycine) for 5 min, and Cdh1 expression was analyzed by Western blotting. We found that Cdh1 protein levels significantly increased in neurons as from 1 hour after glutamate treatment, while no signs of apoptotic death were observed, as assessed by annexin V staining using flow cytometry. However, Cdh1 silencing using the shRNA strategy increased neuronal vulnerability to glutamate treatment, whereas Cdh1 over-expression prevented neurons from excitotoxic damage. Thus, besides its role at regulating cyclins stability in post-mitotic neurons, Cdh1 plays a key neuroprotective role in excitotoxicity. These results may be relevant for understanding the molecular mechanisms involved in certain neurodegenerative diseases.