Quality of life (QoL) in menopause is influenced by many parameters, including vasomotor symptoms, psychological status and culture. The aim of the present study was to examine the association of hormone therapy (HT) with QoL and psychological symptoms in Greek postmenopausal women. The study assessed 216 postmenopausal women (mean age 54.5 years) attending a university menopause clinic in Greece. Fifty-three were users of HT and 163 were not. QoL was evaluated by the Utian Quality of Life Scale (UQOL) and psychological symptoms were assessed by the Symptom Checklist-90-R (SCL-90-R). Women on HT were younger and more educated than women not using HT. Adjusting the analysis for the women's characteristics, HT users had better total UQOL scores than non-users (p < 0.05). Marital status and education had independent effects on QoL, with married and more educated women scoring higher (p < 0.05). Assessment of psychological symptomatology, after adjustment for sociodemographic variables across the different dimensions, revealed that HT users had better SCL-90-R scores than non-users for obsessionality, interpersonal sensitivity and for the general index (p < 0.05). Concluding, even though the impact of sociodemographic and lifestyle variables must be factored into the assessment of QoL, HT use is independently related to an improvement in the total score and in most domains of QoL, and has a significant positive effect on many aspects of psychological well-being in Greek postmenopausal women.