Purpose: We attempt to define the significance and most common causes of new-onset seizures in patients with human immunodeficiency virus (HIV) infection. In addition, we review the seizure type, neurologic examination, and other clinical features to better address diagnostic and management issues in these patients. Patients and Methods: We reviewed 100 cases of new-onset seizures in HIV-infected patients who underwent complete evaluations at the University of California, San Francisco, hospitals. Results: Seizures were the presenting symptom of HIV-related illness in 18 patients, six of whom developed no other HIV-related illness until at least four months after the first seizure. Common causes in the 100 patients included mass lesions, HIV encephalopathy, and meningitis. No cause for the seizures was found in 23 patients despite a complete evaluation. An underlying cause was found in all patients with focal neurologic deficits but in only two of 24 who had normal results on an interictal neurologic examination. Focal ictal features were not predictive of cause. A cause was found in all 12 patients with status epilepticus or medically refractory seizures. A total of 12 of the 87 (14%) patients who received phenytoin developed a hypersensitivity reaction. Despite the brevity of follow-up in some patients, many patients, including those with no definable cause, had multiple seizures prior to the administration of anticonvulsants. Conclusions: The direct effects of HIV on the brain may be the single most common cause of seizures in this population. We favor treatment of a single seizure in patients with HTV infection.