Background: Defaulting from Directly Observed Treatment Short Course (DOTS) is a big challenge to the effective control of TB. There are no published data on defaulting from DOTS in Benin City which necessitated this study to determine the rate of defaulting and identify factors that significantly contribute to defaulting in Benin City, Nigeria. Methods: This was a case control study from August to December 2011 of 1253 TB patients placed on DOTS in Benin City. The two DOTS centres used for the study were situated in University of Benin Teaching Hospital (UBTH) and Egor local government secretariat, both in Egor local government area (LGA) in Benin City. Out of 1253 patients registered on DOTS in the two study centres, 722 patients comprising of 172 defaulters and 550 nondefaulters were selected for the study using the inclusion and exclusion criteria. Logistic regression analysis was performed to determine association between independent variables and defaulting. Results: The default rate was 23.8%. Defaulting was significantly associated with: male sex (OR 3.05; 95%CI 1.60 - 5.80), being married (OR 3.06; 95%CI 1.34 - 6.99), a history of travel (OR 6.87; 95%CI 3.19 - 14.80) and concomitant drug use with TB drugs (OR 1.95; 95%CI 1.02 - 3.73). Conclusion: The default rate from DOTS in Benin City and the factors significantly associated with defaulting have given us some information initially unavailable about defaulting from DOTS in Benin City. TB control programmes taking these factors into consideration need to be done to promote compliance to treatment.