Background: American Indian women in the Northern Plains have a high incidence of cervical cancer. We assessed attitudes on vaccination against human papillomavirus (HPV) in this population. Method: In partnership with two tribal communities, from 2007 to 2009, we surveyed women 18 to 65 years old attending two reservation clinics ("n" = 118 and "n" = 76) and an urban clinic in the same region serving primarily White women ("n" = 158) on HPV knowledge, vaccine familiarity, and willingness to vaccinate children against HPV. We used chi-square tests and binary logistic regression to compare groups and identify correlates of willingness to vaccinate. Results: American Indian women were less knowledgeable about HPV than White women ("p" < 0.001), especially its role in cervical cancer. Willingness to vaccinate children was differentially distributed across the three clinic samples ("p" < 0.001), but this association did not persist after adjusting for demographics and HPV knowledge. Among all samples, more correct answers to HPV knowledge questions was the only factor positively correlated with willingness to vaccinate (odds ratios = 1.2-1.5; "p" < 0.00-0.05). Conclusions: These findings underscore the importance of locally relevant educational interventions to increase HPV vaccination rates among American Indian women.