In Spain little research has focused on assessment of health indicators, both physical and psychological, in people living with HIV. The aim of this study is to evaluate a set of different indicators that allow us to identify psychological factors that may be influencing the quality of life of these people. The sample consist of 744 people infected with HIV aged between from 18 to 82 years (M = 43.04; SD = 9.43). Results show that factors such as self-esteem and leading a healthy lifestyle act as protectors in both, physical and mental health. On the other hand, financial problems, body disfigurement, and depressive mood could have harmful effects on both, physical and mental health. The structural model reveals depressed mood as the factor with greatest influence upon mental health, which in turn can be largely explained by factors such as the stress generated by HIV and personal autonomy. This work has allowed us to identify the vulnerability and protective factors that play a significant role in the physical and mental HRQOL of persons with HIV, providing guidelines for design and implementation of psychological intervention programs aimed to improve HRQOL in this population.