The purpose of this work was to study the prevalence of somatic symptoms in patients with treatment-resistant depression (TRD) and their impact on the response to antidepressant treatment. Somatic symptoms were assessed during the screen visit with the Symptom Questionnaire (SQ) somatic symptom (SQ-SS) and somatic well-being sub-scales (SQ-SWB) in 40 patients with TRD enrolled in a 6-week open trial of nortriptyline. A logistic regression was used to test whether SQ-SS or SQ-SWB scores predicted clinical response to nortriptyline. Ninety-five percent of patients reported at least one somatic symptom. Higher SQ-SS scores during the screen visit predicted poorer response to nortriptyline. There was a trend for lower SQ-SWB scores to predict poor response to nortriptyline. None of the patients with SQ-SS scores above the mean for the sample responded to nortriptyline. The overwhelming majority of patients with TRD presented with somatic symptoms. In addition, a greater number of somatic symptoms during the screen visit placed patients at risk for further treatment resistance.