Headaches are common following smallpox vaccination; the re-introduction of civilian vaccination necessitates better understanding of the clinical features and outcome of postvaccination headache. We identified patients reporting headache following vaccination from among those reported to the U.S. Vaccine Adverse Events Reporting System to characterize demographic and clinical features. One-hundred and eight reports were obtained from among 627 smallpox vaccine-related reports, including 15 hospitalized persons. None had neurologic dysfunction or acute laboratory abnormalities; headache resolved in all except 2 hospitalized patients within 3 months. Severe headache following smallpox vaccination is generally transient, but debilitating headache may occur and further characterization is needed.