BACKGROUND: This study explored whether the prospective associations between muscle strength and incident type 2 diabetes (T2D) differ by varying levels of genetic susceptibility to T2D. METHODS: This study included 141,848 white British individuals from the UK Biobank. Muscle strength was expressed as the relative value of grip strength (measured by a hand dynamometer) divided by fat-free mass (measured via bioelectrical impedance analysis). Three categories of muscle strength (low, medium and high) were generated based on the sex- and age-specific tertiles. Genetic risk of T2D was estimated using a weighted polygenic risk score based on 138 independent single-nucleotide polymorphisms for T2D. During a median 7.4-year follow-up, 4,743 incident T2D cases were accrued. Cox regression with age as the underlying timescale was fit. RESULTS: High muscle strength was associated with a 44% lower hazard of T2D (HR:0.56, 95%CI:0.52-0.60), compared with low muscle strength, after adjustment for genetic risk of T2D. The inverse association between muscle strength and incident T2D was weaker in individuals with high genetic susceptibility. There was evidence of interaction between muscle strength and genetic susceptibility to T2D (p-additive = 0.010, p-multiplicative = 0.046). The estimated 8-year absolute risk of T2D was lower for high genetic risk-high muscle strength (2.47%), compared with low (2.89%) or medium (4.00%) genetic risk combined with low muscle strength. CONCLUSIONS: Higher muscle strength was associated with lower relative risk of developing T2D, irrespective of genetic susceptibility to T2D, while such association was weaker in the high genetic risk group. Individuals at high genetic risk of T2D but with high muscle strength may have a lower 8-year absolute risk of developing T2D, compared with those at low or medium genetic risk but with low muscle strength. Our findings inform future clinical trials to prevent or delay the onset of T2D by implementing muscle-strengthening interventions among individuals of varying levels of genetic susceptibility to T2D, including those with high genetic risk.