The current study examined the Five Cs model of positive youth development (PYD; Lerner et al., 2005) in U.S. Mexican-origin youth (N = 674, 50% female) and tested the extent to which ethnic pride, familismo, and respeto, as an index of cultural orientation, predicted PYD across midadolescence. PYD was modeled using a bifactor structure, which defined global PYD and the Five Cs (Caring, Character, Competence, Confidence, and Connection) using theoretically similar measures matched to the conceptual definitions of the Cs. Tests of longitudinal invariance of the bifactor model at ages 14 and 16 established scalar invariance, providing support for the structure and stability of the Five Cs and global PYD using the theoretically similar measures across time. Adolescents' cultural orientation (latent factor incorporating familismo, respeto, and ethnic pride) at age 14 was positively associated with the Five Cs within and across time. Greater cultural orientation at age 14 predicted increased global PYD across ages 14 and 16. The contribution of cultural orientation to the PYD across midadolescence did not differ by adolescent gender or nativity. These findings demonstrate the robust nature and stability of the Five Cs model of PYD and provide novel evidence that ethnic pride, familismo, and respeto promote greater PYD in Mexican-origin youth during midadolescence.