Background: North American Indigenous (NAI) communities have identified alcohol use as a primary health concern. Experiences of racial discrimination are associated with greater alcohol use, but findings are mixed regarding the role of culture in this relationship. The goal of the present study was to examine the role of culture in the association between racial discrimination and alcohol use. Methods: Across two studies (Study 1: N = 52; Study 2: N = 1743), NAI adolescents living on or near NAI reservations who reported recent alcohol use completed selfreport measures of racial discrimination, cultural affiliation, and alcohol use (e.g., frequency). Results: Bivariate correlations revealed a significant positive association between racial discrimination and alcohol use (Study 1: r = 0.31, p = 0.029; Study 2: r = 0.14, p < 0.001) but not between cultural affiliation and alcohol use. Racial discrimination and cultural affiliation were significantly positively correlated in Study 1 (r = 0.18, p < 0.001), but not in Study 2. Across both studies, the interactions between racial discrimination and cultural affiliation significantly predicted alcohol use in unadjusted models (Study 1: b = 0.70, SE = 0.32, p = 0.033, 95% CI [0.06, 1.33]; Study 2: b = 0.01, SE = 0.01, p = 0.041, 95% CI [0.001, 0.03]), such that the association between racial discrimination and alcohol use was stronger for adolescents reporting high (vs. low) levels of cultural affiliation. In adjusted models controlling for age and sex, the interaction between racial discrimination and cultural affiliation remained significant in Study 2 (b = 0.01, SE = 0.01, p = 0.0496, 95% CI [0.00002, 0.03]) but was no longer significant in Study 1. Conclusions: Findings speak to the need to reduce racial discrimination against NAI youth and to consider youths' different needs based on level of cultural affiliation to reduce subsequent alcohol consumption.