PURPOSE Quality of life (QoL) is an important measure of the burden of disease and could be useful in evaluating patient management and practical interventions. The aim of this study was to explore the association of psychological and clinical variables with QoL in patients with multiple sclerosis (MS). METHODS One hundred and fourteen consecutive patients (mean age 36.1 ± 10.3 years, 72% female) from one MS centre completed the Hospital Anxiety and Depression Scale, the Fatigue Severity Scale and the Short-Form-36 Health Survey (SF-36). Functional disability was assessed using the Expanded Disability Status Scale. Multiple linear regression analyses were performed to analyse demographic, psychological and clinical data. RESULTS Functional disability, depression and fatigue were found to be related inversely to the physical health subscale. Disease course, anxiety and depression were associated negatively with the mental health subscale. CONCLUSIONS Functional disability, depression and fatigue were the main variables related to the perceived physical health subscale, and disease course, anxiety and depression to the perceived mental health subscale in the group of patients with MS. Thus, effective treatment of fatigue, anxiety and depression could be assumed to increase a patient's QoL.