Individuals infected with the human immunodeficiency virus-Type 1 (HIV-1), are at increased risk for neurobehavioral impairment, particularly in later stages of the disease. Even patients in the medically asymptomatic or minimally symptomatic stages of infection may show mild deficits on comprehensive neuropsychological (NP) test batteries, although the clinical significance of such deficits remains uncertain. The present study used vocational difficulties as markers of clinical significance of NP impairment. In a sample of 289 HIV-infected, nondemented men, those who evidenced NP impairment had a higher unemployment rate (p < .001) than did their unimpaired counterparts. In HIV-positive subjects who remained employed, NP impairment was strongly associated with subjective decreases in job-related abilities. Neither depression nor medical symptoms could explain the relationship between the NP impairment and employment problems. These results are consistent with previous studies investigating other neuropsychiatric disorders, which suggest that even mild NP impairment can interfere with employment status. From this standpoint, such impairment in HIV-infected persons may be described as "clinically significant."