BACKGROUND: Monitoring the outcome of tuberculosis (TB) treatment and investigating factors associated with unsuccessful outcome are essential, as unsuccessful treatment fuels resistance to antibiotics. This study aimed to investigate the treatment outcome and associated factors with an unsuccessful outcome at Jimma University Medical Center (JUMC), Southwest Ethiopia. METHODS: A 5-year retrospective analytical study, including all types of TB cases who sought care at JUMC between September 1, 2012, and August 31, 2017, was conducted. Treatment outcomes and TB types were categorized according to the National TB Control guideline. Bivariate analysis was used to analyze the association between treatment outcome and potential variables. RESULTS: Overall data from 1249 patients' records were included in the study. The proportion of male patients was higher (815, 65.3%) than that of females. The mean age (± standard deviation, range) of the cases was 26 (±11. 6, 1-71) years. Of the total, 292 (23.3%) were smear-positive pulmonary TB (PTB), 489 (39.2%) smear-negative PTB, and 468 (37.5%) extra-PTB (EPTB) cases. Available treatment outcomes indicate that 253 (20.2%) were cured, 850 (68.0%) completed therapy, 58 (4.8%) died, 83 (6.6%) defaulted, and 5 (0.4%) failed the therapy. About 76 (5.6%) cases were transferred out and 44 (3.2%) cases were lost to follow-up. In total, 146 (11.7%) patients had an unsuccessful outcome. Unsuccessful treatment outcome was associated with smear-negative PTB (odds ratio [OR] =2.0, 95% confidence intervals [CI] =1.1, 3.7), EPTB (OR = 2.1, 95% CI = 1.2, 3.4), and unknown human immunodeficiency virus (HIV) status (OR = 7.9, 95% CI = 2.5, 25.0). CONCLUSION: The treatment success rate of overall TB patients is lower than end TB Strategy target of ≥90% success rate. Smear-negative PTB, EPTB cases, and those with unknown HIV status tend to have unsuccessful outcome.