To make meaningful cross-cultural comparisons of health-related quality of life (HRQOL) or to pool international research data, it is essential to create culturally unbiased measures that detect clinically important differences between patients. We evaluated the measurement properties of the Functional Assessment of Cancer Therapy-Breast (FACT-B) in 111 Austrian and 144 U.S. patients with breast cancer using item response theory (IRT) methods. A small number of items were identified as displaying statistically significant differential item functioning (DIF), suggesting possible measurement bias. The majority of the items functioned similarly between the two cultural groups. U.S. patients reported lower (worse) physical function and well-being compared with Austrian patients, higher (better) social/family well-being and similar emotional well-being, before and after adjustment for DIF. IRT and related measurement models provide useful methods for assessing cross-cultural equivalence and determining which items can be pooled across languages before analyzing HRQOL data. Determination of clinically significant cross-cultural differences will require additional investigation.