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The present study investigates the measurement invariance of science self-efficacy across sexes among U.S. adolescents using data from the Programme for International Student Assessment (PISA) 2006 and PISA 2015. Employing a multigroup confirmatory factor analysis within the framework set by Kane (2013), this study tests whether the science self-efficacy scale operates equivalently for female and male participants. Findings indicated configural, metric and scalar invariance which revealed that the science self-efficacy scale's items are interpreted similarly across sexes in both PISA 2006 and PISA 2015 and that comparisons of science self-efficacy scores between males and females are valid. These findings suggested the science self-efficacy scale's fairness in assessing science self-efficacy where contributes to the understanding of sex disparities in STEM fields.