The antibody response to the HIV-1 envelope protein has not been well characterized in patients with AIDS dementia complex (ADC). We evaluated the frequency of antibodies against the HIV-1 envelope in cerebrospinal fluid (CSF) and serum from 21 persons with ADC and 10 symptom-free HIV-1-positive subjects using Western immunoblot with reducing and nonreducing buffer and radioimmunoprecipitation (RIP) analysis. RIP analysis revealed anti-envelope antibodies in all sera tested. Higher anti-envelope levels were observed in CSF than in serum of 12 of 21 ADC patients and only 1 of 10 symptom-free subjects (two-sided Fisher exact test, p < 0.05). All persons with moderate to severe ADC had higher anti-envelope levels in CSF than in sera (p < 0.005). CSF anti-gp120 antibodies were not as readily detected by Western blot analysis even under nonreduced conditions, suggesting that they are directed to conformational epitopes. Higher CSF anti-envelope antibodies appear to be more common in patients with ADC than in symptom-free HIV-1-positive subjects. This antibody pattern may serve as a marker for ADC and its progression.