Smallpox is a viral disease unique to humans. To sustain itself, the virus must pass from person to person in a continuing chain of infection and is spread by inhalation of air droplets or aerosols. Twelve to 14 days after infection, the patient typically becomes feverish and has severe aching pains and exhaustion. Some two to three days later, a rash develops over the face and spreads to the extremities. Death usually occurs during the second week. During the first 2 to 3 days of the rash, it may be all but impossible to distinguish between smallpox and chickenpox. However, all smallpox lesions develop at the same pace and, on any part of the body, appear identical. Chickenpox lesions are much more superficial and develop in crops. Smallpox spreads most readily during the cool, dry winter months but can be transmitted in any climate and in any part of the world. The only weapons against the disease are vaccination and patient isolation. Vaccination before exposure or within 2 or 3 days after exposure affords almost complete protection against disease. Vaccination as late as 4 to 5 days after exposure may protect against death. Early detection of cases and prompt vaccination of all contacts is critical because smallpox can only be transmitted from the time of the earliest appearance of rash. Smallpox vaccination is associated with some risk for adverse reactions; the two most serious are postvaccinal encephalitis and progressive vaccinia. Routine vaccination is only recommended for laboratory staff who may be exposed to one of the orthopoxviruses. Smallpox is rated among the most dangerous of all potential biological weapons. 2 figures and 1 reference.