Objective: We sought to identify the role of acculturation in the life satisfaction of Hispanic cancer survivors. Methods: We compared life satisfaction among the high- vs low-acculturated Hispanics who participated in a national, cross-sectional study of quality of life among cancer survivors. Results: Despite fewer socio-economic resources, low-acculturated Hispanic survivors had higher life satisfaction (Beta = 5.08, p<0.05). This relationship was mediated by higher levels of social support and spirituality found among low-acculturated survivors, with spirituality being the strongest predictor (Beta = 0.379, p<0.001). Conclusions: Acculturation may provide opportunities for improved socio-economic status often necessary for adequate functioning in the host culture. However, it may also result in a departure from traditional cultural values, which in turn may negatively impact life satisfaction during cancer survivorship. Copyright (C) 2009 John Wiley & Sons, Ltd.