An outbreak of infection by Coxsackie A-21 virus in a large military base is described. The outbreak occurred in the early fall, traditional time for peak enteroviral infection, but in other respects differed significantly from patterns observed with other enteroviruses. Illness associated with infection was limited to mild undifferentiated respiratory disease. Virus was detected in the throats of infected individuals much more readily than in the lower intestinal tract. Although serologic surveys indicated that prior infection by the virus had been infrequent in the populations studied, neutralizing antibody was shown to confer protection against infection and associated illness. The major differences in infection rates between distinct recruit and "seasoned" groups provided convincing evidence of the significance of factors other than specific viral immunity in the spread of infection.