Central nervous system (CNS) toxicity of tricyclic antidepressants (TCAs) is serious, costly, frequent, and difficult to diagnose early in its course. We first reviewed all published, systematic population studies of such CNS toxicity. Of 976 TCA-treated patients, 58 (6%) developed TCA-induced CNS toxicity. The risk of this toxicity was positively correlated with TCA plasma levels. For levels greater than 450 ng/ml, the risk increased more than 10-fold (to 67%). We further analyzed 36 cases in terms of phenomenology, course, and potential risk factors of TCA-induced toxicity. A protean prodrome involving affective, psychotic, and cognitive symptoms preceded the delirium, which on average took 2 weeks to develop. The variability of this prodrome often leads to erroneous clinical decisions. Risk factors for delirium, in order of importance, included TCA concentration in plasma, age, and female gender.