Background: Because human papillomavirus (HPV) vaccine rates remain low, we evaluated US school nurses' knowledge, attitudes, perceptions of their role as opinion leaders, and professional practice regarding HPV vaccine, and assessed whether knowledge, attitudes, and perceptions of being an opinion leader influenced their professional practice regarding the HPV vaccine. Methods: We used a cross-sectional design by recruiting members from the National Association of School Nurses. All participants (N?=?505) were e-mailed a survey designed for this study. Structural equation modeling (SEM) tested direct and indirect effects. Results: Overall, school nurses had knowledge about HPV and the vaccine, and positive attitudes toward the vaccine. They had less-than-enthusiastic perceptions of their role as opinion leaders regarding the vaccine and implemented few activities related to providing vaccine information. The model revealed a good fit (?[superscript 2]?=?20.238 [df?=?8, p?<?0.01]), with knowledge directly related to attitudes, attitudes directly related to perceptions and practice, and perceptions directly affecting practice. In our model, perceptions functioned as a partial mediator. Conclusions: To enhance school nurses' practice regarding the HPV vaccine, focus should be on increasing positive attitudes toward the vaccine and strengthening perceptions of their role as opinion leaders.