A multicentre comparative clinical evaluation of lofepramine, an imipramine analogue, and imipramine has been made with double-blind technique and fixed dosage (lofepramine 70 mg t.i.d., imipramine 50 mg t.i.d.). Plasma was drawn after 3 weeks for determination of noradrenaline-uptake inhibitory capacity of the parent compound and/or its active metabolites. Plasma concentrations of lofepramine and desmethylimipramine (DMI) were determined in the same samples. The concentrations of lofepramine in the whole material were low (5-27 ng/ml) except for one patient who had a level of 53 ng/ml. In both groups of patients there was an almost 40-fold range in the plasma levels of DMI or apparent DMI. The patients were rated for severity of depression before treatment, then once weekly for 3 weeks and finally during the fifth week. For further information concerning the psychiatric aspects, see d'Elia et al. in this issue (1977). A significant correlation was found between the concentrations of DMI and the noradrenaline-uptake inhibitory capacity in the plasma samples. No correlations were found between uptake inhibitory capacity of plasma samples and the amelioration scores.