Background: Tuberculosis (TB) is one of the most important infectious diseases globally. Case detection and treatment is the main method of prevention and control of TB. Defaulting from Directly Observed Treatment Short Course (DOTS) is a big challenge to the effective control of TB. The upsurge of TB in Nigeria and the poor management control has led to poor treatment outcomes of which defaulting is a major problem. Thus we embarked on this study in Benin City to determine the defaulter rate and factors that are associated with defaulting.Methodology: A retrospective case control study of TB patients placed on DOTS was conducted on 262 patients (99 defaulters and 163 non-defaulters) from August to December 2011. Cases were patients who did not complete treatment (defaulters) and control were patients who completed treatment (non-defaulters). Hospital records of patients placed on treatment from August 2006 to December 2010 were reviewed. From the 1,253 patients placed on treatment between this period, using the inclusion and exclusion criteria in screening patients, we had complete information from 722 patients comprising of 172 defaulters and 550 non-defaulters. From this number, 262 patients were recruited for the study. Data were analyzed using SPSS statistical software. Univariate and multivariate logistic regression analysis to determine association with defaulting was performed. Result: The defaulting rate in this study was 172 (23.8%). Factors significantly associated with defaulting in the multivariate analysis were male sex (AOR 3.05; 95%CI 1.60-5.80), being a civil servant/professional (AOR 0.24; 95%CI 0.08-0.70), being married (AOR 3.06; 95%CI 1.34-6.99), travelled out of locality during treatment (AOR 6.87; 95%CI 3.19-14.80), concomitant drug use with TB drugs (AOR 1.95; 95%CI 1.02-3.73) and occasional counseling about TB by service provider (AOR 0.05; 95%CI 0.01-0.28). In the univariate analysis, no privacy given by health workers showed a significant association with defaulting (OR 2.39; 95%CI 1.39-4.09). Conclusion: The high default rate and the factors significantly associated with defaulting in this study has given us some information initially unavailable about defaulting from DOTS in Benin City and also the challenges faced by patients in the in the course of TB treatment. TB control strategy accorded to these areas is highly recommended.