BACKGROUND: Antiretroviral Treatment (ART) reduces morbidity and mortality in patients with human immunodeficiency virus (HIV). However, clients loss to follow-up (LTFU) from the treatment poses a paramount problem to the public, healthcare, and patient outcome. Thus, this study identified determinants of loss to follow-up to ART among adult clients in West Wollega hospitals, Oromia, Ethiopia, in 2021. METHODS: An unmatched case-control study was conducted and a systematic random sampling technique was used. Data were collected from patient charts by three BSC nurses and three card reporters using a structured checklist. Then, it was entered into Epi-data version 3.1 and analyzed using SPSS version 21. Descriptive statistics (frequency and percentage) were used to present the results. Bivariate and multivariable logistic regression analyses were performed using the backward stepwise method. Adjusted odds ratio (AOR) and p-values <0.05 were used to declare significant association with loss to follow-up. Model fitness was checked using Hosmer-Lemeshow goodness-of-fit. RESULTS: A total of 399 (133 patients and 266 controls) participated in this study. Rural residents (AOR:3.46, 95% CI:1.65, 7.25), male patient (AOR: 2.65 95% CI 1.54,4.55), lack of formal education (AOR: 4.35, 95% CI 1.53, 12.41), base line CD4 ≤350 (AOR: 5.25, 95% CI 1.93,14.24), poor functional status (AOR: 4.298, 95% CI 5.33,34.62) and WHO stages III & IV (AOR: 2.65, 95% CI 1.68,4.19), and tuberculosis co-infection (AOR: 2.82, 95% CI 1.11,7.45) were determinant factors of loss to follow up. CONCLUSION: Rural residence, male sex, daily laborer, no formal education, baseline CD4 count <350 cells/mm3, baseline advanced WHO clinical stage, and TB co-infection were determinants of LTFU. Therefore, emphasis should be given to the identified factors along with awareness creation and health education sessions. Regular TB screening, optimal adherence regardless of their stay on ART, and follow-up study are recommended.