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A strong genetic predisposition for type 2 diabetes mellitus (T2DM) may aggravate the negative effects of low socioeconomic position (SEP) in the etiology of the disorder. This study aimed to examine cross-sectional and longitudinal associations and interactions of a genetic risk score (GRS) and SEP with T2DM and to investigate whether clinical and behavioral risk factors can explain these associations and interactions.We used data from 13,027 genotyped participants from the Lifelines study. The GRS was based on single-nucleotide polymorphisms genome-wide associated with T2DM and was categorized into tertiles. SEP was measured as educational level. T2DM was based on biological markers, recorded medication use, and self-reports. Cross-sectional and longitudinal associations and interactions between the GRS and SEP on T2DM were examined.The combination of a high GRS and low SEP had the strongest association with T2DM in cross-sectional (odds ratio = 3.84, 95% confidence interval = 2.28–6.46) and longitudinal analyses (hazard ratio = 2.71, 1.39–5.27), compared with a low GRS and high SEP. Interaction between a high GRS and a low SEP was observed in cross-sectional (relative excess risk due to interaction = 1.85, 0.65–3.05) but not in longitudinal analyses. Clinical and behavioral risk factors mostly explained the observed associations and interactions.A high GRS combined with a low SEP provides the highest risk for T2DM. These factors also exacerbated each other's impact cross-sectionally but not longitudinally. Preventive measures should target individual and contextual factors of this high-risk group to reduce the risk of T2DM.