The improvement of health related Quality of Life (QOL) has become one of the main objectives of psychological interventions in cancer. The aim of this study was to analyze sociodemographic and psychosocial variables that predict the different components of QOL in a sample of 69 hemato-oncological patients. Depression, social support, disease-related stress situations, coping strategies and optimism were taken as psychosocial predictors. QOL was evaluated with the Short-Form Health Survey (SF-36). With respect to sociodemographic variables, results showed that age and time from the diagnosis were associated with a decrease in QOL, while educational level and having a partner were associated with less pain and better mental health. With respect to negative-affecting psychosocial variables, depression was associated with general health and social functioning, the coping strategy of stoicism was associated with physical and emotional roles, the number of disease-related stress situations was associated with pain, and the feeling of negative emotions associated with the illness was associated with mental health. Social support and optimism were positively associated with vitality. These results have clear clinical implications for psychological interventions aimed to improve QOL in hemato-oncological patients.