Typhoid fever (TF) is a systemic infection caused by the bacterium, Salmonella typhi. Globally, 22 million illnesses and 216,000 deaths occurred annually. The woreda WAS have alerted the outbreak on 27 July, 2016. The objective of this study was to investigate typhoid fever outbreak in Dera Kebele of Ofla woreda, Tigray Region, Ethiopia. Here, a suspected TF case was defined as any person with gradual onset of remittent fever in the first week, headache, arthralgia, anorexia, constipation and or abdominal pain. 45 cases were compared to 90 controls via unmatched case-control study (1:2) using pretested structured questionnaire. Cases were selected randomly. Nine blood and water samples from two sites were collected for microbiological analysis. Data were entered into Epi info 3.5.1 and analyzed using SPSS version 16; multivariate logistic regression was utilized to identify independent factors associated with TF contraction. The significance of association was constructed using odds ratio with its 95% confidence intervals. Results revealed that a total of 98 cases with one death were identified within one week (August 1 to 8, 2016). Overall, 23.2 per 1000 population attack rate with 37 per 1000 population of highest age-specific attack rate in the age group 25-44 were reported. Faecal coliforms were isolated from two water samples and all the nine blood samples were reactive for Salmonella Typhi H (Flagella) and O (somatic) antigen. Not washing hand after toilet [AOR 4.7; 95% CI (1.75-12.6)] and unhygienic house and environment [AOR 3.09; 95%CI (1.36-7.06)] were risk factors for contracting disease but not storing food for later use [AOR .28; 95 %( 0.12, 0.67)] was protective factor. Thus, not washing hand after toilet and unhygienic house and environment were risk factors; hence not storing food for later use was a protective factor. Monitoring environmental sanitation, food hygiene and hand washing practices should be promoted to prevent the disease.