Generalized vaccinia is the result of the systemic spread of vaccinia virus from the smallpox vaccination site. Despite the appearance of the lesions, it is a benign complication of smallpox vaccination. Its frequency is not known, but it is believed to be rare. The literature is confusing, as the term "generalized vaccinia" has been used to describe this benign event as well as more serious and even lethal complications of smallpox vaccination (see eczema vaccinatum, accidental inoculation, and progressive vaccinia).

During the last smallpox vaccination era, most of the patients with generalized vaccinia were children, and most were seen and studied at a time when immunologic knowledge was less complete than at present. Therefore, characteristics that enhance susceptibility are not known for certain. It is likely that many of these children had subtle and minor immunologic abnormalities that permitted some extension of virus spread but not morbid or lethal disease.

The mechanisms underlying apparent viremic spread from a primary vaccination site to other parts of the body are not known. Virus is present in the blood, but clinically only the skin appears to be a target for implantation. Subtle minor immunologic abnormalities, particularly of the immunoglobulin B-cell system, are suspected to be present, but such studies were not available at the time this complication was observed.

The fact that recurrent episodes are seen in some individuals lends credence to an immunologic defect. Antibody deficiency is likely because the lesions result from viremia, which is normally controlled by antibodies. Also, each of the lesions, as well as the primary, heals without incident and in normal fashion, suggesting that cell-mediated immunity is intact.

If an individual has a history suggestive of or an established diagnosis of an antibody (B-cell system) immunodeficiency, they should not be vaccinated. Until the precise underlying cause is identified, it is not possible to predict which patients will be affected, and no preventive measures are known.