Interpersonal factors are of major importance for cancer patients' physical and mental health. Brain tumor patients rank amongst those cancer patients with the highest psychosocial burden. Changes in language, cognition, and personality pose specific risk factors for impeding interpersonal functioning in this patient group. Despite this, role and relevance of social support including both supportive (e.g., emotional support) and detrimental interactions causing distress (e.g., critical remarks) are not well understood. Aims of this study were thus (1) to investigate the association of social support and patients' Health Related Quality of Life (HRQoL) and (2) to assess whether this relationship is mediated by the patients' disclosure behavior. Seventy-four ambulatory brain tumor patients (mean age 54 years; 58% women) completed the following self-report questionnaires: Illness-specific Social Support Scale (SSUK) for assessment of positive support and detrimental interactions, the Disclosure of Trauma Questionnaire (DTQ) for assessment of patients' disclosure behavior, and the Short-Form Health Survey (SF-8) for assessment of QoL. Detrimental social interactions were significantly related to patients' mental and physical well-being while positive support was not. Our results support a model in which patients perceiving detrimental social interactions show more difficulties in talking about illness-specific contents in a functional manner. This, in turn, was associated with a lower physical and mental HRQoL. This was the first study in which the close associations of detrimental social interactions, brain tumor patients' dysfunctional disclosure behavior and patients' mental as well as physical well-being were empiricially validated. Thus, dysfunctional disclosure behavior might pose a relevant therapeutic target when offering psycho-oncological support for brain tumor patients and their families.