While well documented in human immunodeficiency virus (HIV)-1, neurologic sequelae have not been systematically evaluated in HIV-2. After excluding for confounding comorbidities, 67 individuals from a rural cohort in Guinea-Bissau (22 HIV-2 participants, 45 seronegative controls) were evaluated. HIV + individuals were divided into CD4 < 350 and CD4 ≥ 350 for analysis. HIV-associated neurocognitive disorders (HAND), assessed by the International HIV Dementia Scale (IHDS), distal sensory polyneuropathy (DSPN), and myelopathy were the main outcome variables. In univariate analysis, there was no difference in IHDS scores among groups. When analyzed by primary education attainment, IHDS scores were nonsignificantly higher (p = 0.06) with more education. There was no significant difference in DSPN prevalence among groups; overall, 45% of participants had DSPN. There were no cases of myelopathy. In multivariate linear regression, higher IHDS scores were significantly correlated with older age (coefficient = -0.11, p < 0.001). Logistic regression analysis showed that older age (odds ratio (OR) 95% CI 1.04-1.20), lower CD4 count (OR 95% CI 0.996-0.999), and higher BMI (OR 95% CI 1.02-1.43) significantly predicted the presence of DSPN. While a significant increase in cognitive impairment was not observed in HIV-2-infected individuals, the study suggests the IHDS may be a less effective screening tool for HAND in settings of lower educational attainment as encountered in rural Guinea-Bissau. Similar to HIV-1, DSPN seems to occur with lower CD4 counts in HIV-2. Further study of the viral-host interactions in HIV-2 and its consequent neurological diseases may provide an avenue for understanding the epidemic problems of HIV-1.