Complex diseases are presumed to be the result of multiple genes and environmental factors, which emphasize the importance of gene – gene and gene – environment interactions. Traditional parametric approaches are limited in their ability to detect high-order interactions and handle sparse data, and standard stepwise procedures may miss interactions with undetectable main effects. To address these limitations, the multifactor dimensionality reduction (MDR) method was developed. MDR is well suited for examining high-order interactions and detecting interactions without main effects. Like most statistical methods in genetic association studies, MDR may also lead to a false positive in the presence of population stratification. Although many statistical methods have been proposed to detect main effects and control for population stratification using genomic markers, not many methods are available to detect interactions and control for population stratification at the same time. In this article, we developed a novel test, MDR in structured populations (MDR-SP), to detect the interactions and control for population stratification. MDR-SP is applicable to both quantitative and qualitative traits and can incorporate covariates. We present simulation studies to demonstrate the validity of the test and to evaluate its power.