Purpose To examine the natural course and outcome of major depressive disorder (MDD) in primary care over 39 months. Methods Prospective cohort study of 1,338 consecutive attendees with follow-up after 6, 12, and 39 months with DSM-IV MDD using the Composite International Diagnostic Interview (CIDI). We measured severity of depressive symptoms (Patient Health Questionnaire 9), somatic symptoms (Patient Health Questionnaire 15), and mental and physical function (Short Form 12, mental and physical component summary). Analysis of variance and random coefficient models were performed. Results At baseline, 174 people (13%) had MDD of which 17% had a chronic and 40% had a fluctuating course, while 43% remitted. Patients with chronic courses had more severe depressive symptoms (mean difference 6.54; 95% CI 4.38-8.70), somatic symptoms (mean difference 3.31; 95% CI 1.61-5.02), and greater mental dysfunction (mean difference -10.49; 95% CI -14.42 to -6.57) at baseline than those who remitted from baseline, independent of age, sex, level of education, presence of a chronic disease, and a lifetime history of depression. Conclusions Although 43% of patients with MDD attending primary care recover, this leaves a majority of patients (57%) who have a chronic or intermittent course. Chronic courses are associated with higher levels of depressive symptoms and somatic symptoms and greater mental dysfunction at baseline. © The Author(s) 2010.