BackgroundCystic echinococcosis (CE) is a neglected parasitic zoonosis prioritized by the WHO for control. Hygiene education is included in CE control campaigns but appears of little impact, and the precise risk factors for human infection are still uncertain. Several works investigated potential risk factors for CE through questionnaires, mostly carried out on small samples, providing contrasting results. We present the analysis of risk factors questionnaires administered to participants to the largest prevalence study on CE conducted in Eastern Europe.Methodology/Principal FindingsA semi-structured questionnaire was administered to 24,687 people from rural Bulgaria, Romania, and Turkey. CE cases were defined individuals with abdominal CE cysts detected on ultrasound. Variables associated with CE infection at p<0.20 in bivariate analysis were included into a multivariable logistic model, with a random effect to account for clustering at village level. Adjusted odds ratio (AOR) with 95%CI were used to describe the strength of associations. Data were weighted to reflect the relative distribution of the rural population in the study area by country, age group and sex. Valid records from 22,027 people were analyzed. According to the main occupation in the past 20 years, “housewife” (AOR 3.11 [1.51-6.41]) and “retired” (AOR 2.88 [1.09-7.65]) showed significantly higher odds of being infected compared to non-agricultural workers. “Having relatives with CE” (AOR 4.18 [1.77-9.88]) was also associated with higher odds of infection. Dog-related and food/water-related factors were not associated with infection.Conclusions/SignificanceOur results point to infection being acquired in a “domestic” rural environment and support the view that CE should be considered more a “soil-transmitted” than a “food-borne” infection, acquired through a “hand-to-mouth” mechanism. This result helps delineating the dynamics of infection transmission and have practical implications in the design of specific studies to shed light on actual sources of infection and inform control campaigns.AUTHOR SUMMARYCystic echinococcosis (CE) is a parasitic disease with high socio-economic impact, mostly affecting pastoral communities. The causative agent, Echinococcus granulosus sensu lato, is naturally transmitted between dogs and livestock; humans acquire infection through accidental ingestion of parasite eggs. Hygiene education is among the strategies of CE control campaigns, but appears of little impact. “Ingestion of contaminated food/water”, and “contact with dogs” are generally mentioned as the sources of human infection, however actual risk factors are still undefined. Several works investigated potential risk factors for human CE infection through questionnaires, mostly carried out on small samples, providing contrasting results. We analysed 22,027 risk factors questionnaires administered to the participants of the largest prevalence study on CE conducted in Eastern Europe. We found that being “housewife” and “retired” as the main occupation in the past 20 years, and “having relatives with CE” were associated with higher odds of CE infection, while dog-related and food/water-related factors were not associated with infection. Our results indicate that CE may be considered more a “soil-transmitted” than a “food-borne” infection, acquired through a “hand-to-mouth” mechanism in a domestic, rural environment. This may help designing specific studies on pathways of transmission of this neglected parasite.