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In this study, we undertook a detailed neuropsychological analysis of a cohort of long-term HIV-1 positive individuals in conjunction with sequencing of the mitochondrial genome. Stepwise regression analysis identified sub-haplogroup as one of the strongest predictors of psychomotor speed and dexterity function over time since the start of therapy. Consistent with this, patients with haplogroup L3e obtained better scores on psychomotor speed and dexterity tasks relative to the remainder of the cohort, suggesting that this haplogroup provides a protective advantage to these individuals when faced with the combined stress of HIV-1 infection and long-term antiretroviral therapies. Differential performance on declarative memory tasks was noted for individuals with other sub-L haplogroups, but these differences were not as robust as the association between L3e and psychomotor speed and dexterity tasks. This work provides evidence that mitochondrial haplogroup impacts differential sensitivity to neurological dysfunction among patients in chronic disease settings, such as HIV-1 infection.