Context and Purpose: This study's objectives are to: investigate potential additive and multiplicative influences of rurality and race/ethnicity on chronic physical illness in a nationally representative sample of youth; and examine intra-Latino processes using a Latino sub-sample. Specifically, we examine how rurality and individual psychosocial processes reflected by acculturation proxies (generational status and use of the English language at home) link to chronic physical illness of Latino youth. Finally, we examine whether these associations and the levels of chronic illness differ across Latino subgroups. Methods: Logistic-normal (binomial) modeling analyses examine multilevel influences on physical health using longitudinal data from a nationally representative sample (N = 13,905) of white, African American, Latino, Asian, and Native American adolescents between the ages of 12 and 19 participating in the National Longitudinal Study of Adolescent Health. Findings: Prevalence rates of certain chronic illnesses (obesity, asthma, and high cholesterol) among Latino adolescents exceed rates for the same illnesses among white adolescents. Comparisons between rural and non-rural youth reveal a rurality disadvantage in terms of any chronic illness likelihood among Latino, Asian, and Native American youth not evident among whites or African Americans. Among Latino youth (N = 2,505), Mexican Americans show lower health risk for any chronic illness compared to other Latino groups. However, third generation Latinos and those who primarily speak English at home experience higher risk for any chronic illness than do those of first or second generation status, with amplification of the risk linked to English use at home among Latino youth living in rural areas.