Blood concentrations of triglycerides are influenced by genetic factors as well as a number of environmental factors, including adiposity and glucose homeostasis. The aim was to investigate the association between a serum triglyceride weighted genetic risk score (wGRS) and changes in fasting serum triglyceride level over 5 years and to test whether the effect of the wGRS was modified by 5 year changes of adiposity, insulin resistance, and lifestyle factors. A total of 3,474 nondiabetic individuals from the Danish Inter99 cohort participated in both the baseline and 5 year follow-up physical examinations and had information on the wGRS comprising 39 genetic variants. In a linear regression model adjusted for age, sex, and baseline serum triglyceride, the wGRS was associated with increased serum triglyceride levels over 5 years [per allele effect = 1.3% (1.0-1.6%); P = 1.0 × 10(-17)]. This triglyceride-increasing effect of the wGRS interacted with changes in insulin resistance (Pinteraction = 1.5 × 10(-6)). This interaction indicated that the effect of the wGRS was stronger in individuals who became more insulin resistant over 5 years. In conclusion, our findings suggest that increased genetic risk load is associated with a larger increase in fasting serum triglyceride levels in nondiabetic individuals during 5 years of follow-up. This effect of the wGRS is accentuated by increasing insulin resistance.