The aim was to assess the health-related quality of life (HRQL) of the Roma and further to detect the significant determinants that are associated with their HRQL. The cross-sectional study involved 1068 Roma adults living in settlements (mean age 36). HRQL was measured by the Greek version of SF-36 Health Survey and further socio-demographic characteristics (sex, age, marital status, education, permanent occupation etc.) and housing conditions (stable housing, access to basic amenities such as drinkable water, drainage, electricity which compose material deprivation) were involved. Non parametric tests and multiple linear regression models were applied to identify the factors that have significant association with HRQL. After controlling for socio-demographic characteristics, health status and housing conditions, sex, age, education, chronic diseases, stable housing and material deprivation were found to be significant determinants of the Roma’s HRQL. Men reported significantly better health than women as well as those who attended school compared to the illiterate. Chronic diseases were remarkably associated with poor HRQL from 10 units in MH (Mental Health) to 34 units in RP (Role Physical). Material deprivation was related to lower GH (General Health), and VT (Vitality) scores and higher RP (Role Physical) and RE (Role Emotional) scores. Chronic conditions and illiteracy are two key areas that contribute significantly to worse HRQL. Policies should be part of a comprehensive and holistic strategy for the Roma through intervention to education, housing and public health.