BackgroundAn epidemic of Hepatitis E infection occurred in Kitgum district, northern Uganda in 2009. In that epidemic, more than 10,422 people were infected, and over 166 deaths were registered. Kitgum District Health Management Information Systems (HMIS) showed that Hepatitis E cases continued to occur in Mucwini more than in Kitgum Matidi sub-county despite instituting similar epidemic control measures in the two communities. The tenacity of the virus in Mucwini sub-county had remained unclear. This study aimed to assess communities’ views and perspectives on the differential prevalence of Hepatitis E in the two sub-counties of Kitgum Matidi and Mucwini in northern Uganda.MethodsA mixed study using qualitative and quantitative methods was used. Four Focus group discussions and six key informant interviews were conducted with the village health teams, local council chairpersons, health workers, and community members. These participants were chosen purposively because of their expertise and experience in community health services. Face-to-face interview guides were administered to obtain detailed information on factors associated with the differential occurrence of Hepatitis E in the two sub-counties. This study was approved by a local IRB and the Uganda National Council of Science and Technology (UNCS&T).ResultsThe most substantial findings were the differences in prevention and control practices in the two communities. Residents of Mucwini were less compliant with infection, prevention, and control guidelines, and disagreements between local councilors and village health teams in Mucwini over allowances led to poor implementation and non-adherence to guidelines on community control of the epidemic.ConclusionA differentially higher prevalence of Hepatitis E in Mucwini than in Kitgum Matidi resulted from poor personal and community hygiene and non-adherence to behavior change communication among residents of Mucwini than their counterparts in Kitgum Matidi. The authors recommend a more proactive approach to managing an epidemic by securing the willingness of the affected community to adopt appropriate infection prevention and control guidelines. In addition, disagreements among stakeholders should be resolved quickly so that all community members adhere to control measures.