Background: Many patients with non-cardiac chest pain or benign palpitations have poor prognosis in terms of symptom persistence, limitations in everyday activities, and reduced health-related quality of life (HRQOL). Aims: The aims of the study were to evaluate the changes and impact of illness perceptions during a three-session cognitive behavioural therapy (CBT) intervention for patients with non-cardiac chest pain or benign palpitations. Method: Patients with persistent complaints 6 months after a negative cardiac evaluation were invited to participate in a randomized controlled trial. Patients in the intervention group (n = 21) received three manualized sessions with CBT, including one physical activity exposure session; the control group (n = 19) received usual care from their general practitioner. Brief Illness Perception Questionnaire (BIPQ) was used to measure illness perceptions. Patients were assessed at start and end of the intervention and at 3- and 12-month follow-up. Results: The intervention and control group differed significantly on five of the eight items of BIPQ at least at one follow-up assessment. At end of treatment and at 3-month follow-up change in illness concern (Item 6 in BIPQ) mediated about 40% of the change in depression from baseline, and at 12-month follow-up about 50% of the change in depression was mediated by change in personal control (Item 3 in BIPQ). Conclusion: Illness perceptions measured with BIPQ may mediate the short and long term treatment effects of a three-session CBT-programme for patients with non-cardiac chest pain and benign palpitations.