By and large, the immune systems of people infected with HIV are being protected and maintained by advances in highly active antiretroviral therapy; as such, this is extending the lives of people into old age. Unfortunately, for many living with this disease, HIV is associated with neuroinflammation, co-morbidities, and accelerated aging which can compromise brain function, resulting in cognitive deficits. The purpose of this article is to highlight how to interpret these deficits within the framework of neuroplasticity and cognitive reserve for this clinical population. We suggest several recommendations for cognitive rehabilitation and mitigation such as addressing lifestyle factors, psychostimulants, cognitive remediation therapy, and treatment of depression and anxiety. Implications for nursing research and practice are posited.