OBJECTIVE The quality of life (QOL) of patients with coronary artery disease (CAD) is known to be impaired. Non-cardiac chest pain referrals are often under-diagnosed and untreated, and there are hardly any studies comparing the QOL of CAD and panic disorder related (non-cardiac) chest pain referrals (PDRC). METHODS We assessed the psychiatric morbidity and QOL of patients newly diagnosed with CAD (n = 40) at baseline and six weeks post-treatment and compared their QOL with patients with PDRC (n = 40) and age- and gender-matched healthy controls (n = 57). Psychiatric morbidity in the CAD group was assessed using the General Health Questionnaire (GHQ12) item, Hamilton Anxiety Scores (HAM-A), and Hamilton Depression Scores (HAMD). QOL measures were determined by the World Health Organization QOL questionnaire (brief) and Seattle Angina Questionnaire. The CAD group was treated with anti-ischemic drugs (nitrates, betablockers), antiplatelet drugs (acetylsalicylsalicylic acid), anticoagulants (low molecular weight heparin, clopidogrel), and managed for risk factors. The PDRC group was treated with selective serotonin reuptake inhibitors and anxiolytics. RESULTS Patients with panic disorder had a worse QOL than those with CAD and healthy controls in the physical domain and psychological domain (PDRC vs. CAD vs. healthy controls, p < 0.001). In the CAD group, smoking was associated with change in angina stability (p = 0.049) whereas other tobacco products were associated with change in angina frequency (p = 0.044). Psychiatric morbidity was present in 40.0% of patients with CAD. In the PDRC group, a significant correlation of HAM-A scores was noted in the physical (p = 0.000), psychological (p = 0.001), social (p = 0.006), and environment (p = 0.001) domains of QOL. Patients with panic disorder had a significant improvement in anxiety scores after treatment compared to baseline (HAM-A scores difference 21.0 [16.5-25.6]; p < 0.001). CONCLUSIONS Patients in the PDRC group had a worse QOL than those in the CAD and healthy control groups. This highlights the need for careful diagnosis and prompt treatment of panic disorder in these patients to improve their QOL. Additionally, smoking, the use of other tobacco products, and hypercholesterolemia were associated with angina symptoms in patients with CAD.