Fifty-two patients with acquired immunodeficiency syndrome were enrolled in this study to evaluate the relationship between cerebrospinal fluid (CSF) zidovudine concentrations and neurologic and human immunodeficiency virus (HIV) culture findings. Paired HIV-CSF culture and neurologic measurements were available in 30 and 45 patients, respectively. Twenty-nine patients were assessable for zidovudine CSF concentrations. Patients underwent lumbar puncture and neurologic testing before and after 8 weeks or more of oral zidovudine therapy (600 to 1500 mg/d). After 8 weeks of therapy, the frequency of HIV isolation from CSF cultures was unchanged. Significant neurologic improvement by examination was noted in 61.5% (32/52) of the patients. The median CSF zidovudine concentration among 29 patients was 0.047 mg/L (range, 0.015 to 0.198 mg/L). No correlation between CSF zidovudine concentration, cumulative dose, or HIV isolation from CSF and persistence or resolution of neurologic symptoms or signs was observed. The mechanisms by which zidovudine improves neurologic function are unclear and appear unrelated to direct clearance of virus from CSF.