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In this study, we analyzed baseline data for 278 HIV-infected participants with comprehensive neurological and neurocognitive evaluations to examine the contribution of DSP and anatomic distribution of neuropathic signs (upper extremity or lower extremity) on standardized domain scores. We found that participants with DSP performed significantly worse in multiple domains containing timed psychomotor tests (i.e., motor, information processing speed and executive functioning). With regard to executive functioning, differences were limited to a test with a motor component (Trail Making Test, Part B). The group with clinically detectable neuropathic signs in the upper extremities and the group with signs limited to the lower extremities both performed worse in the motor domain than the group without DSP. Participants with DSP demonstrated a unique pattern of impairment limited to neuropsychological domains with timed psychomotor tests. These results suggest that caution should be used in interpretation of neuropsychological tests in patients with DSP, as some abnormalities may be exacerbated by peripheral nervous system pathology. 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