The present study explores the effect of topic interest and knowledge on comprehension and their relationship in L2 reading. Given this issue has been studied almost exclusively with fluent L1 readers, it seems necessary to investigate the applicability of the findings from previous studies to L2 reading. In order to enhance the generalizability, the present study employed multiple texts and tasks. The subjects were 126 Korean adult EFL learners representing various academic backgrounds and wide range of English proficiency. Results showed that the effect of knowledge and interest on L2 reading comprehension varied greatly depending on task type, suggesting that any conclusion drawn about the effect of prior knowledge or interest on reading comprehension could be biased depending on the task used to assess the construct. In addition, knowledge of topic vocabulary was the most stable factor of reading comprehension regardless of text structure or measure of reading comprehension. The association between topic interest and topic knowledge proved very weak in general unlike in L1 reading, not supporting schema-theoretic views about the effect of topic interest and its relationship with topic knowledge. More results and discussions are presented along with the statement of limitations and implications both theoretical and practical.