In multicultural context of health care, health providers’ ethnocentrism and English language skills play a crucial role in effective and appropriate intercultural communication. This study aims to explore the relationship between ethnocentrism and investment in English language learning in the multi-ethnic context of English language classrooms at Iranian medical universities. Thus, the levels of ethnocentrism and investment in English language learning of 200 Iranian medical students were measured using General Ethnocentrism Scale and Investment in English Language Learning Scale. The findings of the present study showed that despite the participants’ relatively moderate levels of ethnocentrism and investment, the two constructs strongly and negatively correlated with each other. That is, the more ethnocentric the participants were, the less invested in English language learning they were. Further, the relationship between ethnocentrism and investment, and different contextual factors such as linguistic loyalty, intercultural friendship, sense of legitimacy, and social comfort in multi-ethnic English classes were investigated. The results showed that social comfort had the strongest relationship with the degree to which the participants invested in English language learning in multi-ethnic classes. Practical implications, direction, and limitations are discussed.