Abstract Background Traditionally tricyclic antidepressants (TCAs) have an important place in treatment of major depressive disorder (MDD). Today, often other antidepressant medications are considered as first step in the pharmacological treatment of MDD, mainly because they are associated with less adverse effects, whereby the position of TCAs appears unclear. In this study we aimed to examine the current practice of TCAs in treatment of unipolar MDD. Methods A mixed methods approach was applied. First, a selection of leading international and national guidelines was reviewed. Second, actual TCA prescription was examined by analyzing health records of 75 MDD patients treated with the TCAs nortriptyline, clomipramine or imipramine in different centers in the Netherlands. Third, promotors and barriers influencing the choice for TCAs and dosing strategies were explored using semi-structured interviews with 24 Dutch psychiatrists. Results Clinical practice guidelines were sometimes indirective and inconsistent ...