The invention provides H—NOX proteins for the delivery of oxygen to hypoxic tissue following stroke. H—NOX proteins extravasate into hypoxic penumbra associated with stroke and preferentially accumulate for sustained delivery of oxygen to the hypoxic tissue to ameliorate adverse affects of stroke related hypoxia. In some embodiments, the H—NOX comprises PEGylated H—NOX and non-PEGylated H—NOX.