ObjectiveAlthough typhoid fever is a major public health problem in Ethiopia, data is not available in the study area. Therefore, this study aimed to determine the prevalence, clinical presentation at the time of diagnosis and associated factors of typhoid fever among febrile patients visiting Shashemene Referral Hospital, southern Ethiopia. A cross-sectional study was conducted from January 1, 2016, to October 30, 2016. Socio-demographic and clinical data were collected using a structured questionnaire. A blood sample was collected and inoculated into Tryptic soy broth.ResultsA total of 421 adult febrile patients suspected of typhoid fever were included in the study. Of these, the overall prevalence of culture-confirmed typhoid fever was 5.0% (21/421). The prevalence of typhoid fever was significantly associated with rural residence (8.4%). As compared to the urban resident, the rural resident was 3.6 times more likely found to have culture-confirmed typhoid fever. The prevalence of typhoid fever was significantly associated with those patients whose water source was spring 7 (12.3%) and river 7 (13.2%). All of those study participants who used treated water were culture negative. Fever for ≥ 5 days, abdominal pain, and skin rash independently predicted blood culture-confirmed typhoid fever.