A fatal vaccination reaction is reported in an infant 3 months of age, characterized by the continuous enlargement of time original vaccination and progressive development of new lesions. Virologic and histologic logic examinations indicated that the lesions were caused by vaccinia virus. Clinical and laboratory findings suggested that the disease was associated with agammaglobulinemia and defects in the immune mechanism. Differential features of this disease, generalized vaccinia and variola are presented in the discussion. The infant's blood appeared to lack γ-globulin. Nevertheless, the serum yielded positive results in the hemagglutination inhibition and neutralization tests, though not in the complement fixation test. Some of the reactive substances in the serum, especially the neutralizing substances, were probably antibodies passively acquired. Pathologically, the disease was characterized by lymphopenia, absence of healing and lack of inflammatory response. The infant was treated unsuccessfully with γ-globulin and plasma from recently vaccinated donors. Successful treatment of this condition has recently been reported by the use of antivaccinal γ-globulin.