OBJECTIVE To evaluate the effects of treatment with alternating and simultaneous regimens of zidovudine and didanosine on neuropsychological function in patients with symptomatic HIV-1 disease, focusing on patients with possible HIV-1-associated central nervous system (CNS) compromise at entry. METHODS Randomized non-blinded clinical trial. METHODS Government medical research center. METHODS Thirty-eight patients with symptomatic HIV-1 disease, of whom 21 had evidence of CNS compromise at entry. RESULTS After 12 weeks of therapy, overall significant improvements in memory (P < 0.01) and focused attention (P < 0.001) were seen on both regimens. These gains, however, were largely limited to those patients with HIV-1-associated CNS compromise at entry (P < 0.05). Improvements were also noted in receptive vocabulary, reading, perceptual discrimination and reasoning, divided attention, motor strength, and in mood and affect. Improvements in those latter functions were generally of limited magnitude and were of comparable size for both compromised and non-compromised patients. There was no overall difference between the two drug regimens in the effects on CNS parameters. CONCLUSIONS Therapy-related improvements were noted particularly for patients with HIV-1-associated CNS compromise. Neuropsychological functions that have been implicated in AIDS dementia--memory and attention--showed the greatest gains. In contrast to the previously described superiority of the simultaneous regimen with regard to immunologic and virologic parameters, there was no difference between the regimens with regard to CNS measures. This supports the contention that the CNS constitutes a relative independent compartment in terms of HIV disease and treatment.