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Abstract Background Large introductory lecture courses are frequently post-secondary students’ first formal interaction with science, technology, engineering, and mathematics (STEM) disciplines. Grade outcomes in these courses are often disparate across student populations, which, in turn, has implications for student retention. This study positions such disparities as a manifestation of systemic inequities along the dimensions of sex, race/ethnicity, income, and first-generation status and investigates the extent to which they are similar across peer institutions. Results We examined grade outcomes in a selected set of early STEM courses across six large, public, research-intensive universities in the United States over ten years. In this sample of more than 200,000 STEM course enrollments, we find that course grade benefits increase significantly with the number of systemic advantages students possess at all six institutions. The observed trends in academic outcomes versus advantage are strikingly similar across universities despite the fact that we did not control for differences in grading practices, contexts, and instructor and student populations. The findings are concerning given that these courses are often students’ first post-secondary STEM experiences. Conclusions STEM course grades are typically lower than those in other disciplines; students taking them often pay grade penalties. The systemic advantages some student groups experience are correlated with significant reductions in these grade penalties at all six institutions. The consistency of these findings across institutions and courses supports the claim that inequities in STEM education are a systemic problem, driven by factors that go beyond specific courses or individual institutions. Our work provides a basis for the exploration of contexts where inequities are exacerbated or reduced and can be used to advocate for structural change within STEM education. To cultivate more equitable learning environments, we must reckon with how pervasive structural barriers in STEM courses negatively shape the experiences of marginalized students.