In spite of several approaches and therapeutic measures, treatment-resistant depression (TRD) continues to inflict serious, individual and collective consequences. Therefore, there is a persistent need to scrutinize the concept of TRD in order to adapt the therapeutic strategies.To estimate the incidence of TRD in patients with a first major depressive episode (MDD), and study factors associated with resistance.A descriptive prospective longitudinal study of outpatients with a first MDD, was conducted. Patients with a history of subthreshold hypomania were excluded. Eligible patients were put on a selective serotonin reuptake inhibitor (SSRI), either fluoxetine or sertraline. Participants were followed regularly until they had a therapeutic response or they met the criteria for TRD.The study involved 82 adults. The incidence of treatment-resistant depression was 19.4% CI95%=[5.5-33.3]. Among the sociodemographic and clinical factors, family history of psychosis (p=0.038) and chronic respiratory comorbidities (p=0.016) were associated with TRD. The small size of the sample is a potential limitation of this study. Besides, the use of only two SSRIs could influence the results.In this study, the incidence of TRD was at the lower limit of the rates reported in clinical studies. Clinical factors associated with TRD suggest the relevance of genotype analysis to identify patients with TRD. Furthermore, our results highlight the importance of heeding comorbidities to optimize care. Larger multicenter studies are needed to generalize.