The relationship between therapeutic response and the urinary excretion of norepinephrine and its metabolites by depressed patients before and during treatment with imipramine or desimipramine has been examined. Those patients who excreted the lesser quantities of 3-methoxy-4-hydroxyphenylglycol (MHPG) prior to drug treatment had the best response to medication. Similar relationships were not found for metanephrine, normetanephrine, or vanillymandelic acid (VMA). Those patients who responded best excreted greater quantities of normetanephrine and MHPG during drug treament, relative to the predrug period, and those patients who responded least well had a decrement in the excretion of these two metabolities. There were significant decrements in the quantities of VMA and metanephrine excreted in urine during drug treatment but these changes were unrelated to the therapeutic response. The theoretical and practical implications of these findings are discussed.