Because few physicians today have seen a case of smallpox, a summary of its clinical course is warranted. Smallpox is usually spread person-to-person in virus-laden droplets expelled from the oropharynx. The infection begins with seeding of the virus in the upper respiratory tract and regional lymph nodes, followed by involvement of the skin and internal organs (3, 7–8). After a 7- to 17-day incubation period (mean, 10 to 12 days), clinical onset begins with a 3-day pre-eruptive stage that most commonly includes fever, malaise, headache, and backache. The exanthem generally starts on the face and spreads over the body in a centrifugal distribution, with greater involvement of the face and extremities than the trunk. A hallmark of the smallpox rash is its monomorphic appearance, with lesions appearing essentially as a single “crop” and evolving together through different stages as erythematous macules, papules, vesicles, pustules, and crusts. Vesicles often develop a central umbilication that persists into the pustular stage. The enanthem of smallpox appears as erythematous macules that evolve into papules and vesicles and may involve the oropharynx, tongue, and nasal cavity. The rash resolves over 14 to 21 days, leaving disfiguring, pitted scars (with a predilection for the face) in more than half of typical cases of variola major. Complications of smallpox include encephalitis, pneumonitis, pneumonia, secondary cutaneous infection, arthritis, conjunctivitis, keratitis, and corneal ulceration (which can lead to blindness).