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High school students’ course-taking in mathematics and science is an important aspect of preparing them for science, technology, engineering, and mathematics (STEM) majors in college. Applying cluster analysis, this study identifies four distinctive mathematics and science course-taking patterns of high school students in terms of course subject and corresponding durations of taking courses measured by Carnegie credits. Results from multinomial regression and a logistic regression analysis with adjusted standard error for nested data structure show that students’ demographic and school background variables predict students’ course-taking patterns and that course-taking patterns are closely related to their college enrollment in STEM majors.