The biological role of quiescin sulfhydryl oxidase 1 (QSOX1) in tumor development is not well known, and its relation to breast cancer progression and prognosis is controversial. Here, our aim was to study the expression pattern and prognostic impact of QSOX1 in breast cancer, in relation to molecular subgroups and tumor cell proliferation. We examined a population-based series as part of the prospective Norwegian Breast Cancer Screening Program, including all women (50-69 years) diagnosed with breast cancer in one county of Norway during 1996-2003. QSOX1 expression was assessed by immunohistochemistry on tissue microarrays (n=458). Median follow-up time was 13 years. High expression of QSOX1 protein was associated with features of poor prognosis including high histologic grade, hormone receptor negativity, HER2 positivity, and increased tumor cell proliferation. High QSOX1 expression was further associated with reduced breast cancer-specific survival in both univariate and multivariate analysis, independent of molecular subtypes. High QSOX1 expression is a strong and independent factor of reduced survival in breast cancer, also reflected by elevated levels in more aggressive molecular subgroups. QSOX1 expression may represent a biomarker for aggressive disease and a potential treatment target.