The use of English as a medium of instruction (EMI) in higher education is considered a vehicle in non-English-speaking countries for the purpose of internationalization, enhancing students' employability, and international competition. Many higher education institutions in Europe adapted their curriculum and started teaching in English, while enrolling international students from Erasmus programs and non-European countries. This study builds on an EMI course set within a Belgian university. Six students whose second language was English were interviewed to identify and explore their motivation, difficulties, and instructional support as it relates to their spoken interaction during the class. The findings revealed that (a) students' motivation and willingness to communicate during English-as-a-second-language spoken interaction was related to their English language self-efficacy, the study topic, and the learning environment; (b) students' spoken interaction seemed restricted due to difficulties including academic language use, understanding the academic content, and their attitudes toward the learning activity; and (c) instructional support, namely, social-emotional, cognitive, and language support, was perceived by students to boost their willingness to communicate and confidence to be involved in spoken interaction.