The new onset of headache in a person infected with human immunodeficiency virus (HIV) may be an ominous sign of a significant underlying neurological disorder. This case control study compares the prevalence of headache in HIV-seropositive persons without identifiable neurological disease on study entry to that in an HIV-seronegative control population with similar risk factors for HIV infection. Features of headache that were evaluated included frequency, duration, location, severity, and recent change in characteristics. In the HIV-seropositive population, the presence of headache and its specific features were correlated with the degree of immunosuppression as determined by absolute CD4 counts and Centers for Disease Control stages, the presence of other neurological symptoms and neurological signs, cranial magnetic resonance imaging (MRI) findings, and cerebrospinal fluid (CSF) values. Headaches were common; approximately 50% of all subjects reported headache at study entry and 2 years later. Headache frequency and characteristics were not different between HIV-seropositive and HIV-seronegative subjects. Headache was neither more frequent nor different in HIV-seropositive individuals with advanced immunosuppression. There was no correlation between headache and abnormal CSF parameters, cranial MRI abnormalities, including the presence of sinusitis, or the use of zidovudine.