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Abstract Typhoid fever continued to be the key cause of morbidity and mortality in developing countries with poor hygienic practices and limited access to safe drinking water. The Widal card agglutination test is the main diagnostic tool in Ethiopia, which is limited in differentiating the overlapping symptoms with other acute febrile illnesses such as malaria and viral enteritis. This eventually leds to unnecessary antibiotic use and eventual drug resistance. Therefore this study wants to assess the burden and associated potential risk factors of typhoid fever among suspected cases using the typhoid rapid stool antigen test in Northeast Ethiopia. A hospital-based cross-sectional study was conducted at Gaint and Meket Shediho primary hospitals from May to July 2021. A total of 255 patients clinically suspected of typhoid fever, and willing to grant informed consent were included systematically. The demographic and hygiene-related variables were collected using a pre-tested structured questionnaire. The rapid stool antigenic test and xylose-lysine-deoxycholate agar (XLD) stool culture were evaluated for the level of agreement. The present study indicated that the prevalence of typhoid fever was 15.3%. This displayed that the human-restricted infectious disease, typhoid fever remained a challenge to Ethiopians. Washing hands with soap, history of typhoid fever, having previous history of hospitalization, and chronic underlying disease was the significant potential factor for typhoid fever. The higher agreement of the rapid stool antigenic test with the stool culture can indicate the factual burden of typhoid fever in the suspected population. This could minimize empiric treatment and the possible emergence of drug resistance. Thus, resource-poor settings may need to look for a rapid and reliable stool antigenic test.