Prospective longitudinal health-related quality of life (QOL) data from 161 women newly diagnosed with breast cancer were compared to age-adjusted mean QOL scores from a general female population (n=949). In addition, multiple factors (demographic, personality trait, participation in treatment decision-making, information satisfaction, and medical data), which previous research has indicated affect the QOL of breast cancer patients, were simultaneously investigated in a multivariate model, in order to determine which of these variables have the strongest influence on QOL one year after surgery. QOL was evaluated with the EORTC QLQ-C30 at time of diagnosis, three- and 12-months postoperatively. Women with breast cancer scored significantly lower on emotional, cognitive, and social functioning (p < 0.01) at time of diagnosis compared to the general female population, and continued to score lower on cognitive (p=0.008) and social (p=0.009) functioning one-year after surgery. In addition to the initial QOL, breast conservation surgery was predictive of better physical functioning (p=0.01) and body image (p < 0.0001), while chemotherapy was predictive for poorer role functioning (p=0.01) one year after surgery. Dispositional optimism was predictive for better emotional (p=0.003) and social functioning (p=0.01) one year after surgery. At time of diagnosis and throughout the post-diagnosis period, dispositional optimism was associated with better QOL and fewer symptoms.