OBJECTIVE: To investigate the burden of pertussis in American Indian and Alaska Native (AI/AN) infants. STUDY DESIGN: AI/AN pertussis-associated hospitalizations between 1980 and 2004 were evaluated using Indian Health Service (IHS)/tribal inpatient data, which include all reported hospitalizations within the IHS/tribal health care system. RESULTS: Between 1980 and 2004, 483 pertussis-associated hospitalizations in AI/AN infants were documented; 88% of cases involved infants age < 6 months. For this entire period, the average annual hospitalization rate was 132.7 per 100,000 AI/AN infants (95% confidence interval [CI] = 121.3 to 145.2), and 234.5 per 100,000 AI/AN infants age < 6 months (95% CI = 213.1 to 258.1). Between 2000 and 2004, the annual hospitalization rate was 100.5 per 100,000 AI/AN infants (95% CI = 81.6 to 123.7), which exceeds the estimated 2003 pertussis hospitalization rate of 67.7 per 100,000 in the general US infant population (95% CI = 61.9 to 73.5). The highest pertussis hospitalization rates in 2000 to 2004 were in AI/AN infants in the Alaska and Southwestern IHS regions of the United States. CONCLUSIONS: The burden of pertussis in AI/AN infants is high, particularly so in infants age < 6 months in the Alaska and the Southwestern IHS regions of the United States. Ensuring implementation of vaccination strategies to reduce the incidence of pertussis in AI/AN, infants, adolescents, and adults alike is warranted to reduce the burden of pertussis in AI/AN infants.