Although most unipolar depression clinical guidelines advise against evaluating the efficacy of antidepressant pharmacological treatment until it has been administered in therapeutic doses for a minimum of 4–6 weeks, there is an increasing tendency to make therapeutic decisions after only 2 weeks of treatment. We present a study which aim is to determine whether the clinical course, following 2 weeks of antidepressant treatment, allows therapeutic decisions to be made for patients affected by a moderate/severe depressive episode. The study has an 8-week, prospective, observational design in which all consecutive in- and outpatients with moderate/severe unipolar major depression aged over 17 years received antidepressant treatment based on a standardized treatment protocol. Clinical status was assessed at baseline and at 2-, 4-, and 8-weeks. The final sample consisted of a total of 114 subjects. In our sample, the rate of remitters versus non-remitters was similar between the 2-week improvers and the 2-week non-improvers. It should also be emphasized that it was not possible to explain, based on the epidemiological and clinical characteristics assessed, which 2-week non-improvers would tend towards remission and which would show a partial or full response. Based on these results, for patients affected by a moderate/severe unipolar depressive episode, it would not be appropriate to make new therapeutic decisions following 2 weeks of anti-depressive pharmacological treatment depending on whether the patient has shown clinical improvement or not.