The health consequences of rapid cultural and economic change have been explored for adults in a range of low-income countries, but comparable research in children and adolescents is currently lacking. Concurrently, the immunosuppressive effects of psychosocial stress have been documented in Western populations, but have yet to be considered in cross-cultural contexts. This study uses lifestyle incongruity (inconsistency between a household's material style of life and its socioeconomic status) as a model of culture change and stress, and considers its impact on immune function in a sample of 230 10-20 year-olds from (Western) Samoa. Anthropometric, lifestyle, and psychosocial data were collected, as well as finger prick blood spot samples for analysis of C-reactive protein (marker of infection) and antibodies against the Epstein-Barr virus (marker of cell-mediated immune function). Controlling for potential confounders, adolescents from households with a material style of life that exceeds its socioeconomic status have reduced cell-mediated immune function, indicating an increased burden of psychosocial stress. Social relationships moderate this effect: lifestyle incongruity stress is pronounced among adolescents with a high degree of social integration, and absent in adolescents with low social integration. This finding is counter to the buffering role of social support reported in previous applications of lifestyle incongruity to adults, and suggests that the moderating role of social integration may be unique to adolescents. The potential utility of the lifestyle incongruity model for future cross-cultural studies of child and adolescent stress is discussed.