Background: Behavioural activation might be a viable alternative to antidepressant medication for major depressive disorder. Aims: To compare the effectiveness of behavioural activation and treatment as usual (TAU, antidepressant medication) for major depressive disorder in routine clinical practice in Iran. Method: Patients with major depressive disorder (n = 100) were randomised to 16 sessions of behavioural activation (n = 50) or antidepressant medication (n = 50) (IRCT138807192573N1). The main outcome was depression, measured with the Beck Depression Inventory (BDI) and the Hamilton Rating Scale for Depression (HRSD), assessed at 0, 4, 13 and 49 weeks. Results: Symptom reduction was greater in the behavioural activation group than in the TAU group on both the BDI and the HRSD at 13 and 49 weeks in multilevel analysis. Baseline depression severity was a moderator, with relatively better effects for behavioural activation in individuals who were more severely depressed. Also, there was better retention in the behavioural activation than in the TAU group. Conclusions: Behavioural activation is a viable and effective treatment for people with major depressive disorder, especially for those who are more severely depressed, and it can successfully be disseminated into routine practice settings in a non-Western country such as Iran. Copyright © BJP 2013.