Respiratory diphtheria was one of the most common causes of death among children in the pre-vaccine era. Since the introduction of diphtheria toxoid vaccine in 1920s, and its widespread use by the late 1940s, diphtheria became increasingly rare in the United States. However, through the 1970s diphtheria remained endemic in some states, with reported incidence rates > 1.0 per million population in six states (Alaska, Arizona, Montana, New Mexico, South Dakota, and Washington). Starting in 1980, less than five cases have been reported each year in the United States. The majority of culture-confirmed cases have been associated with importation from other countries. Toxigenic Corynebacterium diphtheriae, the organism causing diphtheria, was thought to have become rare or even have disappeared from previously endemic areas such as South Dakota. However, during four months in 1996, 11 persons (one index case, six patients and four household contacts) in an American Indian community in South Dakota were found to be infected by C. diphtheriae; six of these isolates were toxigenic. The findings in this report indicate that despite 20 years without reported respiratory diphtheria cases, toxigenic C. diphtheriae is still present in South Dakota. The continuous circulation of toxigenic strains of C. diphtheriae emphasizes the need for health care providers throughout South Dakota to promote timely vaccination against diphtheria among persons of all ages and ethnic groups, to be aware of the clinical signs and symptoms of diphtheria so that cases can be promptly diagnosed and treated, and further public health measures can be taken to contain this serious disease.