Comorbid substance use in individuals with serious mental illness (SMI) is considered a risk factor for treatment discontinuation. There are limited studies on the association of khat (Catha edulis F) chewing, a common practice in Ethiopia and Eastern Africa, with treatment discontinuation. The objective of this study was to assess the influence of khat chewing on treatment discontinuation among people with serious mental illness at Amanuel Mental Specialized Hospital, Addis ababa, Ethiopia. Cross sectional study was undertaken. Data was collected using semi structured questionnaire and data abstraction format from patient’s medical record. A total of 805 with 405 khat chewer and 400 non-chewer individuals with SMI were involved in the study. The data was analysed using SPSS V-23; binary logistic regression was used and p value less than 0.05 in multivariate analysis was considered significant. The prevalence of treatment discontinuation was 34.3% without significant difference between khat chewer and non-chewer individuals (p = 0.445). Treatment discontinuation was significantly associated with relapse and suicide ideation. The odds of treatment discontinuation was 2.3 times higher in relapsing individuals compared to the nonrelapsing individuals with serious mental illness, AOR (95% CI) of 2.3 (1.6 - 3.5). The odd of treatment discontinuation was 1.7 times higher in individuals with suicidal ideation compared to those who don not have suicide ideation, AOR (95% CI) of 1.7 (1.2 -2.5). In conclusion one third of patients with SMI had treatment discontinuation. Relapse and suicide ideation, which were associated with treatment discontinuation, increases hospitalization and associated treatment burden in individuals with SMI. There should be mechanism to closely follow patients at community level to detect and manage treatment discontinuation as early as possible.