We aimed to investigate the association between weight change from 20 years of age and insulin resistance (IR), and genetic and environmental relationships between these traits. In 594 Korean twins and family members (209 men, 385 women, 44.0 ± 10.8 years old), the percentage of weight change was calculated using self-reported body weight at 20 years of age and currently measured bodyweight. IR traits were assessed using fasting plasma glucose and insulin, the homeostasis model assessment of IR index (HOMA-IR), and the quantitative insulin sensitivity check index (QUICKI). Linear mixed analysis was applied after adjusting for household, body mass index (BMI) at the age of 20 years, age, sex, alcohol, smoking, physical activity, and caloric intake. Heritabilities and genetic and environmental correlations were estimated after adjusting for covariates. In 55 monozygotic twin pairs discordant for HOMA-IR level by >0.3, a conditional logistic regression analysis was conducted regarding weight change. Increases in glucose, insulin, and HOMA-IR and a decrease in QUICKI were associated with a higher percentage of weight change (p < .05). Estimated heritabilities for IR traits were 0.401-0.606 (p < .001). In cross-trait relationships, environmental correlations were -0.43-0.42 (p < .05 for all IR), while genetic correlations were -0.27-0.27 (p < .05 for QUICKI, insulin, and HOMA-IR). In 55 pairs of monozygotic twins, the odds ratio (95% confidence interval) for having a higher level of HOMA-IR was 1.10 (1.03-1.17) with 1% increase in weight change since 20 years old, after adjusting for lifestyle-related factors. In conclusion, both genetic and environmental influences played significant roles in the positive association between weight change from 20 years of age and IR.