Acculturation to U.S. culture by Latinos and Asian Americans has been associated with increased prevalence of substance abuse. However, little is known about the association between acculturation and substance use among Arab Americans, or more specifically, among Arab-American treatment clients. In 156 Arab-American male treatment clients, we found that higher levels of U.S. acculturation were positively associated with increased prevalence of polysubstance abuse. This first report on a large series of Arab-American clients also found considerable within-group variability. These results can be used to develop treatment plans and work-force training on the importance of U.S. acculturation and variability within Arab Americans.