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Guided by situated expectancy-value and mindset theories, we investigated how students’ science mindsets are associated with motivational beliefs (expectancies, values including cost) and achievement via effort comparisons in chemistry. Gender differences in these mediational pathways were examined. We recruited a sample (N = 620) of students in undergraduate introductory chemistry courses. Multiple-group SEM revealed the powerful roles of science mindsets for women’s motivation and performance in chemistry. Results suggest that (a) protective roles of a science growth mindset and detrimental roles of a science fixed mindset in outcomes were particularly salient for women in chemistry and (b) effort comparisons acted as a mechanism of a science fixed mindset for undermining women’s motivation and performance in chemistry.