Background: Metabolic syndrome [MetSyn] is a combination of physiological risk factors that can trigger physical and emotional problems. The aim of this study is to investigate whether MetS is associated with lower health related quality of life (HRQoL) and depression. Methods: New consecutive patients referred to an outpatient lipid clinic for evaluation of possible MetSyn were eligible for inclusion in the study. The MetSyn was defined according to the International Diabetes Federation (IDF) diagnostic criteria. The Medical Outcomes Study, Short Form-36 (SF-36) was used to assess HRQoL. Anxiety and depressive symptoms were assessed by a validated Greek version of the Hospital Anxiety and Depression Scale (HADS). Multivariate regressions were used to assess the hypothesis. Results: Three hundred and fifty-nine subjects were involved of whom 206 [57.4%] met the diagnostic criteria for the MetSyn (?cases?) and 153 [42.6%] did not (?comparator group?). Comparisons of SF-36 scores between patients with and without MetSyn revealed statistically significance differences except of bodily pain subscale [Physical Functioning: 78.4 vs 87.8, Role Physical: 66.8 vs 85.5; General Health: 59.8 vs 70.4; Vitality: 59.6 vs 68.0; Social Functioning: 76.5 vs 83.8; Role Emotional: 69.3 vs 82.6, Mental Health: 60.8 vs 71.7]. A predominance of anxiety [60%] and depressive symptoms [67%] was observed among subjects with MetSyn. Patients with MetSyn undergoing a therapeutic approach showed no improvement in its general and mental health [p: NS]. Conclusions: The presence of MetSyn was associated with more impaired HRQoL as well as depressive behaviours.