Major adverse reactions interrupting drug therapy during treatment of 84 patients with desipramine hydrochloride were studied to determine their relationship to desipramine plasma concentrations and other clinical variables. The frequency of adverse reactions was higher in patients over 60 years old (39%), and in patients also receiving antipsychotic medications (32%), but low in patients under 60 years old (7%). Desipramine plasma concentrations in patients having side effects did not differ significantly from those in patients without side effects. Steady state desipramine plasma concentrations did not increase with age. Symptomatic orthostatic hypotension, the most common side effect encountered, occurred early in treatment at low desipramine plasma concentrations. Other side effects, usually described as anticholinergic, occurred exclusively in the 34 patients receiving both desipramine and antipsychotic drugs. The concentration of 2-hydroxy-desipramine, the total concentration of 2-hydroxy-desipramine and desipramine, and the ratio of 2-hydroxy-desipramine to desipramine were not higher in 11 patients having side effects than in a comparison group without side effects.