Many researchers and practitioners consider ethnic segregation in neighbourhoods or schools detrimental to migrants’ acculturation in host societies. Empirically, however, segregation is a 'mixed bag' and its effects depend crucially on the investigated acculturation domain (e.g., negative for language skills, positive for well-being). As most prior studies have focused on a restricted spectrum of acculturation, a comprehensive assessment within one single study is needed to establish comparability across different acculturation domains. Among over 8000 immigrant-background students from four countries, we investigated the association of classroom segregation, defined as opportunities for contact with natives and other migrants, with a broad spectrum of acculturation (academic, attitude-related, identity-related, social, health-related, and psychological criteria). Some findings were consistent (e.g., academic acculturation), some were contrary to prior research (e.g., social acculturation). In sum, our results shed light on the 'mixed bag' of segregation and contribute to the understanding of a crucial social issue.