Abstract: Background: How to define clinical significance of antidepressants has become a matter of far-reaching clinical and regulatory consequences. A mean difference of at least 3 points on the Hamilton Depression Rating Scale (HAMD-17) between active treatment and placebo has been proposed as cut-off score for clinical significance in antidepressant trials.Objective: We aimed to present arguments that this, and other commonly used related approaches to establish clinical significance are likely to be misleading and risky depriving patients with mild depression of efficient treatments.Methods: These problems are exemplified with the data from a randomized placebo-controlled five-arm clinical trial with primary care patients with milder depressive syndromes (MIND-study).Results and conclusions: Designs for studying clinical significance have to be distinguished from those assessing efficacy. Moreover, evaluation of the clinical significance of psychotherapy as a possible alternative to antidepressants faces the problem of how to define a valid control group where blinding of neither therapists nor patients is possible.