BACKGROUND: Evidence suggests a deterioration of health-related quality of life (HRQL) after breast cancer diagnosis and therapy. This study examines sociodemographic and health-related factors that could be associated with the HRQL of working women with breast cancer during the first five years after primary surgery. Second, it explores potential vulnerable groups with respect to HRQL using decision tree analyses. METHODS: Women diagnosed with breast cancer who had paid work at diagnosis were recruited at 11 breast cancer centers in the Hannover region, Germany, after primary surgery. Assessments took place four times. 455 patients completed mailed questionnaires at 3 weeks after primary surgery. Women were followed up at 6 months, 1 year and on average 5 years after primary surgery. The physical and mental wellbeing dimensions of HRQL were examined through the Short-Form health survey-12. Potential associations between HRQL and health and sociodemographic factors were examined using multiple linear regression. Classification tree analyses were applied to define specific vulnerable groups. RESULTS: Mastectomy (ß=-2.49; CI:-4.67, -0.30) and chemotherapy (ß=-4.25; CI:-7.04, -1.46) as health related factors were significantly associated with poorer physical wellbeing at 3 weeks and 6 months after primary surgery, respectively. Returning to work (RTW) after having been on sick leave was strongly associated with better HRQL as illustrated by higher sum scores for physical (at 3 weeks: ß=6.21; CI:3.36, 9.05; at 6 months: ß=5.40; CI:3.01, 1.80; at 1 year: ß=8.40; CI:5.31, 11.49) and mental wellbeing (at 6 months: ß=6.03; CI:33.25, 8.81; at 1 year: ß=7.71; CI:4.85, 10.58) until 1 year after primary surgery. However, its significant effect was no more apparent at 5 years after primary surgery. At that stage, income was mostly associated with physical (ß=0.002; CI:0.0002, 0.003) and mental wellbeing (ß=0.002; CI:0.0005, 0.003) with higher summary scores for higher income especially in women aged ≤ 61 years. In addition, living with a partner appeared to be an important positively associated factor with better mental wellbeing in women with breast cancer (at 6 months: ß=3.68; CI: 0.72, 6.63; at 5 years: ß=2.85; CI:0.39, 5.32) and the first splitting node that defined vulnerability at 5 years. CONCLUSIONS: HRQL in breast cancer appears to be a multidimensional phenomenon associated with disease, treatment and social factors. A special focus should be drawn to women with lower income and those not living with a partner when planning rehabilitation programs and strategies that aim to improve the long term HRQL in breast cancer. As RTW appeared to be positively associated with HRQL, future research should examine potential causal relationships between RTW and HRQL in breast cancer in order to provide evidence needed to plan prevention strategies that aim to improve HRQL after breast cancer.