Major neurocognitive changes occur during adolescence, making this phase as one of the most critical developmental period of life. Furthermore, this phase in life is also the time in youth substance use has its onset. Several studies demonstrated the differential associations of alcohol and cannabis use concerning the neurocognitive functioning of both males and females. Past and contemporary literature on gender-specific effects in neuroscience of addiction is predominantly based on cross-sectional datasets and data that is limited in terms of measurement (...) variability. Given the importance of gender-specific effects in addiction studies, and in order to address the two above-mentioned gaps in the literature, the present study aimed to compare neurocognitive functioning of male and female adolescents in the context of cannabis and alcohol use, while employing a longitudinal design with multiple repeated measurements. Participants were 3,826 high school students (47% female; mean age, 12.7), which were recruited from 31 high schools in the greater Montreal area. Participants were requested to complete annual surveys for five consequent years, from 7th to 11th grade, assessing their alcohol/cannabis use and neurocognitive functioning (working memory, delayed recall memory, perceptual reasoning, and inhibition control). The analytical strategy was focused on the longitudinal association between each predictor (female, male) and each of the outcomes (domains of neurocognitive functioning). Multilevel linear models assessed the association of alcohol and cannabis consumption and the four domains of neurocognitive functioning. Results revealed a gender by within-subject interaction, suggesting a weaker effect of yearly fluctuation of cannabis use on working memory among males compared to females. Our findings suggest a different pattern of neurocognitive impairment of female and male working memory after using cannabis over the course of adolescence. Early initiation of cannabis use potentially results in more spatial working memory deficits in female adolescents. This may negatively influence young females’ capacity in academic settings and lead to significant impairment in adulthood, which critically decreases the individual’s quality of life. (shrink)