PURPOSE: The aim of the study was to determine if epidemiology instruction for high school students can improve science literacy skills compared with other science, technology, engineering, and math courses. METHODS: The Test of Scientific Literacy Skills (TOSLS), a validated measure of scientific inquiry and interpretation, was used to assess the change in students' (n = 116; 63% female, 36% Asian, 30% Hispanic, 54% 12th grade, 48% mid poverty, and 24% high poverty) science literacy skills based on pre-post performance. RESULTS: Multilevel models adjusted for individual-level student gender, race-ethnicity, grade level, age, semester, and poverty status showed similar TOSLS performance for physics (β = 0.58; 95% confidence interval [CI], -0.44 to 1.61), biology (β = 0.09; 95% CI, -0.82 to 1.00), and statistics (β = -0.76; 95% CI, -1.84 to 0.32), and lower for chemistry (β = -1.09; 95% CI, -2.26 to 0.08) and geology (β = -1.04; 95% CI, -2.06 to -0.02) relative to the reference group, epidemiology. Models testing the interaction of course subject and sociodemographic factors did not show gender differences in TOSLS performance for epidemiology, in contrast with physics (lower in females) and biology (higher in females). CONCLUSIONS: Study findings suggest that epidemiology may be an appropriate method for supporting high school students' development of science literacy skills, although larger and more nuanced studies are needed.