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Abstract: Background: Over 60% of patients with major depressive disorder (MDD) do not respond fully to therapy. Half of them eventually will not respond at all and will be referred to as treatment resistant depression (TRD) patients. Stressful life events were found to be associated with MDD and were also found to affect the course of the disease. We hypothesize that negative life events might be an independent risk factor for TRD. Methods: One hundred and seven unipolar MDD patients, all treated for at least 4 weeks, were enrolled in the study. Patients were assessed on their psychiatric and medical history, and seven categories of stressful life events. Results: 39.3% of participants were defined as TRD patients and 60.7% as non-TRD. TRD patients had more severe depression, more past suicide attempts, more hospitalizations, longer episodes, and received more benzodiazepines, antipsychotics, and ECT. Job loss and financial stress were more prevalent among the TRD group. Overall, the TRD patients had more negative life events than responders. Limitations: This is a retrospective study. In addition, the definition of TRD was done dichotomically, therefore the association between number of stressful life events and the degree of resistance was not tested. Conclusions: Job loss and financial distress were found to predict TRD. The loss of a parent and severe health conditions were not associated with TRD, suggesting that events affecting the development of MDD, do not necessarily affect the treatment outcome. [Copyright &y& Elsevier]