Background It is well acknowledged that antiretroviral therapy (ART) discontinuation hampers the progress towards achieving the UNAIDS treatment targets that aim to treat 90% of HIV diagnosed patients and achieve viral suppression for 90% of those on treatment. Nevertheless, the magnitude, trend and risk factors for ART discontinuation have not been explored extensively. We carried out a retrospective data analysis to assess prevalence, trend and risk factors for ART discontinuation among adults in Southwest Ethiopia. Methods 12 years retrospective cohort analysis was performed with 4900 HIV-infected adult patients between 21 June 2003 and 15 March 2015 registered at the ART clinic at Jimma University Teaching Hospital. ART discontinuation could be loss to follow-up, defaulting and/or stopping medication while remaining in care. Because data for 2003 and 2015 were incomplete, the 10 years data were used to describe trends for ART discontinuation using a line graph. We used binary logistic regression to identify factors that were correlated with ART discontinuation. To handle missing data, we applied multiple imputations assuming missing at random pattern. Results In total, 4900 adult patients enrolled on ART, of whom 1090 (22.3%) had discontinued, 954 (19.5%) had transferred out, 300 (6.1%) had died, 2517 (51.4%) were alive and on ART, and the remaining 39 (0.8%) had unknown outcome status. The trend of ART discontinuation showed an upward direction in the recent times and reached a peak, accounting for a magnitude of 10%, in 2004 and 2005. Being a female (AOR = 2.1, 95%CI: 1.7-2.8), having an immunological failure (AOR = 2.3, 1.9-8.2), having tuberculosis/HIV co-infection (AOR = 1.5, 1.1-2.1) and no previous history of HIV testing (AOR = 1.8, 1.4-2.9) were the risk factors for ART discontinuation. Conclusions One out of five adults had discontinued from ART, and the trend of ART discontinuation increased recently. Discontinued adults were more likely to be females, tuberculosis/HIV co-infected, with immunological failure and no history of HIV testing. Therefore, it is vital to implement effective programs such as community ART distribution and linkage-case-management to enhance ART linkage and retention.