Background: HPV is associated with several cancers, yet HPV vaccine uptake rates remain suboptimal. Enhancing HPV vaccine promotion requires looking beyond individual characteristics and conducting a thorough evaluation of how health-related and health system factors may influence HPV vaccine uptake. Purpose: Our study explores the relationship of health-related and health-system factors with patient-centered communication, HPV-related knowledge, and perceived effectiveness of the HPV vaccine. Methods: We used data from HINTS 5, Cycle 1, and performed structural equation modeling to explore the impact of health-related and health system factors on perceived HPV vaccine effectiveness, both directly and via HPV knowledge and patient-centered communication. The predictors in our model included health-related factors and health-system factors. Results: Findings suggest a direct relationship between HPV knowledge and perceived vaccine effectiveness ([beta] = 0.73; p < 0.05), and patient-centered communication and perceived vaccine effectiveness ([beta] = 0.07; p < 0.05). Frequency of doctor visits directly and negatively predicted patient-centered communication ([beta] = -0.04, p < 0.05). Self-reported health status was directly and positively related to HPV vaccine acceptability ([beta] = 0.147, p < 0.05). Having a chronic condition ([beta] = -0.09, p =< 0.05) and depression/anxiety ([beta] = 0.141, p < 0.05) was related to HPV vaccine acceptability, via knowledge. Discussion: These findings enhance our nuanced understanding of the intricate interplay between health-related and health-system factors in shaping perceptions and attitudes toward HPV vaccination. Translation to Health Education Practice: Accounting for health-related and health system factors is essential for effective dissemination of HPV information.