We investigated the relations between affiliation with Mexican culture and self-esteem at baseline (Time 1 [T1]), and internalizing symptoms 2 years later (Time 2 [T2]) among a sample of high-risk Mexican American adolescents. Results indicated that T1 affiliation with Mexican culture was not related to T2 internalizing symptoms, controlling for T1 internalizing symptoms. The relation between T1 self-esteem and T2 internalizing symptoms was significant, controlling for T1 internalizing symptoms. Regression analyses revealed, for girls only, a significant interaction between affiliation with Mexican culture and self-esteem in the prediction of T2 internalizing symptoms. Specifically, low self-esteem was a risk factor for internalizing symptoms only among those girls minimally affiliated with Mexican culture. There was no significant interaction between cultural affiliation and self-esteem among Mexican American boys. Findings highlight the importance of gender and culture in risk processes for internalizing symptoms.