Objective Genome-wide association studies have identified genetic variants associating with BMI, however, it is un-clarified whether the same variants also influence body weight fluctuations. Design and Methods Among 3,982 adult individuals that attended both a baseline and a five year follow-up examination in the Danish Inter99 intervention study, we constructed a genetic risk score (GRS) based on 30 BMI variants to address whether it associated with body weight changes. Moreover, we examined whether the effect of lifestyle changes was modulated by the GRS. Results The GRS associated strongly with baseline body weight, with a per risk allele increase of 0.45 (0.33-0.58) kg (P = 2.7 × 10(-12) ), corresponding to a body weight difference of 3.41 (2.21-4.60) kg comparing the highest (≥ 30 risk alleles) and lowest (≤ 26 risk alleles) risk allele tertile. No association was observed with changes in body weight during the five years. Changes in lifestyle, including physical activity, diet and smoking habits associated strongly with body weight changes, however, no interactions with the GRS was observed. Conclusion The GRS associated with body weight cross-sectionally, but not with changes over a five year period. Body weight changes were influenced by lifestyle changes, however, independently the GRS.