Epaulette sharks inhabiting reef platforms are exposed to hypoxic and hyperoxic cycles. The adaptive mechanisms used to prevent neurological damage during these cycles have not been examined. Nitric oxide has a neuroprotective role in some hypoxia-tolerant species. We examined epaulette brains following a severe experimental hypoxic regimen (0.39 mgO2/l for 2 h) and compared nitric oxide synthase (NOS) expression with that in normoxic controls using NADPH-diaphorase staining. Intense NOS activity occurred in microvasculature following exposure to a severely hypoxic environment in contrast to the low levels seen in controls. We established for the first time that the epaulette shark was hypoxia-tolerant because there was no delayed phase of neuronal apoptosis. Enhanced NOS production in response to hypoxia may cause vasodilation, which would maintain the appropriate metabolic environment for continued neuronal survival during exposure to hypoxia.