Increasing numbers of non-travel-associated hepatitis E virus (HEV) infections have been reported in Europe in recent years. Our objective was to review the evidence on risk factors and transmission routes of autochthonous HEV infection and hepatitis E in Europe in order to develop recommendations for future research, prevention and control. A systematic literature review was performed to identify all primary reports and studies published during 1998–2008 on hepatitis E in humans and animals in Europe by searching Pubmed, reference lists of major articles and international conference proceedings. Each of the 106 included studies was categorized into one of three evidence levels (EL) based on study design and diagnostic methodology. The evidence was generally weak (73 were assigned to EL1, two to both EL1 and EL2, and 30 to EL2), further compounded by the use of poorly validated serological assays in some studies. Only one case-control study was assigned to EL3. Persons with autochthonous hepatitis E infection were on average older than the general population and predominantly male. There was no evidence for one main transmission route of HEV infection or risk factor for hepatitis E. However, zoonotic transmission seemed likely and person-to-person transmission too inefficient to cause clinical disease. Multiple routes of transmission probably exist and should be further investigated through analytical studies and reliable diagnostic kits. Based on current evidence that points to zoonotic transmission from pigs, thorough cooking of all porcine products, prevention of cross-contamination in the kitchen and improved education for occupationally exposed people (e.g. pig farmers, veterinarians and sewage workers) may help prevent HEV infection. Although evidence for parenteral transmission is limited, it is recommended that a risk assessment is undertaken.