The relationship between prior knowledge of and interest in a topic is complex. Althoughknowledge and interest may often go hand in hand, they do not necessarily correlate. Thepurpose of this study was to separate the effects of prior knowledge and topic interest on secondlanguage reading comprehension. Participants in the study were 104 students of English as asecond language in an English-for-academic-purposes program at a large American university.On the basis of a prior-knowledge test and a topic-interest inventory, each student read passagesand took multiple-choice comprehension tests on topics for which they had all four possiblecombinations of high and low topic interest and high and low prior knowledge. Results on thereading comprehension measure for the two main effects of prior knowledge and topic interest,although in the expected direction, did not reach significance, possibly because of a significantinteraction between those two variables. There was also a significant effect for Englishproficiency level, as well as a significant interaction between interest and gender, with malesmore influenced by high topic interest than females. Our results are compared to those of otherfirst and second language studies that have explicitly investigated the interrelationships amongtopic interest, prior knowledge, and gender.