Background: Globally, cervical cancer is the fourth most common cancer in women with more than 85% of the burden in developing countries. In Uganda, cervical cancer has shown an increase of 1.8% per annum over the last 20 years. The availability of the Human Papillomavirus (HPV) vaccine presents an opportunity to prevent cervical cancer. Understanding how the health system influences uptake of the vaccine is critical to improve it. This study aimed to assess how the health systems is influencing uptake of HPV vaccine so as to inform policy for vaccine implementation and uptake in Mbale district, Eastern Uganda. Methods: We conducted a cross sectional study of 407 respondents, selected from 56 villages. Six key informant interviews were conducted with District Health Officials involved in implementation of the HPV vaccine. Quantitative data was analyzed using Stata V.13. Prevalence ratios with their confidence intervals were reported. Qualitative data was audio recorded, transcribed verbatim and analyzed using MAXQDA V.12, using the six steps of thematic analysis developed by Braun and Clarke. Results: Fifty six (14%) of 407 adolescents self-reported vaccine uptake. 182 (52.3%) of 348 reported lack of awareness about the HPV vaccine as the major reason for not having received it. Receiving vaccines from outreach clinics (p = 0.02), having many options from which to receive the vaccine (p = 0.02), getting an explanation on possible side-effects (p = 0.024), and receiving the vaccine alongside other services (p = 0.024) were positively associated with uptake. Key informants reported inconsistency in vaccine supply, inadequate training on HPV vaccine, and the lack of a clear target for HPV vaccine coverage as the factors that contribute to low uptake. Conclusion: We recommend training of health workers to provide adequate information on HPV vaccine, raising awareness of the vaccine in markets, schools, and radio talk shows, and communicating the target to health workers. Uptake of the HPV vaccine was lower than the Ministry of Health target of 80%. We recommend training of health workers to clearly provide adequate information on HPV vaccine, increasing awareness about the vaccine to the adolescents and increasing access for girls in and out of school.

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