<b><i>Background:</i></b> Psychotherapy patients can be more or less disabled by their psychological symptoms. The present study investigated whether mentalization and self-efficacy contribute to the association between psychological symptom severity and disabilities in activities and participation. <b><i>Methods:</i></b> The data of 216 psychotherapy inpatients were examined in a cross-sectional design. Bootstrapping-enhanced mediation analyses were performed to investigate whether self-efficacy and mentalization are mediators between psychological symptom severity and disabilities in activities and participation. The Hamburg Modules for the Assessment of Psychosocial Health-49 were used to measure psychological symptom severity and self-efficacy, mentalization was assessed with the Mentalization Questionnaire, and disabilities in activities and participation were operationalized with the ICF-Mental-A &amp; P questionnaire. <b><i>Results:</i></b> Mentalization as well as self-efficacy functioned as mediators between psychological symptom severity and disabilities in activities and participation (<i>p</i> < 0.05). They were equally strong mediators, and both remained significant mediators when statistically controlling for the other mediator (<i>p</i> < 0.05). <b><i>Conclusions:</i></b> Mentalization as well as self-efficacy explain a significant proportion of the relationship between psychological symptom severity and disabilities in activities and participation. Working on mentalizing and self-efficacy might be important mechanisms to reduce disability due to symptoms. The cross-sectional design is a limitation of the study.