Our aim was to identify the risk factors associated with unsuccessful outcomes of tuberculosis (TB) treatment in patients diagnosed between 2014 and 2016 in the 125 municipalities of Antioquia, Colombia. We studied a retrospective cohort of patients with TB diagnosed between 2014 and 2016, from national routine surveillance systems, in 125 municipalities of Antioquia. Factors associated with unsuccessful tuberculosis treatment outcomes (treatment failed, lost to follow up, or death) were identified utilizing a Poisson regression with robust variance. Over 3 years, of the 6,739 drug-susceptible tuberculosis patients, 73.4% had successful treatment and 26.6% unsuccessful outcomes (17% lost to follow up, 8.9% deaths, and 0.7% treatment failures). Patients with subsidized health insurance (Relative risk [RR]: 2.4; 95% CI: 2.1-2.8) and without health insurance (RR: 2.5; 95% CI: 2.1-3.0) had a higher risk for unsuccessful tuberculosis treatment compared to those with contributive health insurance. Other risk factors included age over 15 years, male sex, homelessness, people living with HIV, previous treatment, and primary diagnosis during hospitalization. Protective factors were living in a rural area and extrapulmonary disease. It is important to generate strategies that improves tuberculosis diagnosis in primary healthcare institutions. In addition, it is imperative to initiate new research about the barriers and obstacles related to patients, healthcare workers and services, and the health system, including the analysis of urban violence, to understand why the goal of TB treatment success has not been reached.