In adapting to the host society, immigrant adolescents may have problems negotiating the challenges of acculturation. The factors that promote and those that hamper psychological adaptation may not play the same role in all ethnic groups. Our study focuses on psychological adaptation of two main immigrant groups in Spain that differ in cultural distance to the host society and level of societal acceptance: adolescents of Moroccan and Ecuadorean origin. Our findings show, first, that mainstream cultural orientation is positively related to psychological adaptation, whereas perceived ethnic discrimination is negatively associated with adaptation. Second, the relationship between ethnic cultural orientation and psychological adaptation and between length of residence in Spain and adaptation is stronger for the Moroccan youth than for their Ecuadorean peers. Theoretical and practical implications of these results are discussed. This manuscript was prepared and written while the first author was affiliated to the University of Cordoba in Spain and financially supported by the Spanish Ministry of Science and Innovation within the framework of a National Program of Human Recourses' Mobility (I+D+I 2008-2011). Data collection was financially supported by the Spanish Ministry of Science and Technology (I+D BSO2003-09222).