To determine the association between 20-year trajectories in insulin resistance (IR) since young adulthood and appendicular lean mass (ALM) at middle-age in adults without diabetes. A prospective cohort study was designed among young and middle-aged US men (n?=?925) and women (n?=?1193). Fasting serum glucose and insulin were measured five times in 1985-2005. IR was determined using the homeostasis model assessment (HOMA). ALM was measured in 2005 and ALM adjusted for BMI (ALM/BMI) was the outcome. Sex-specific analyses were performed. Three HOMA-IR trajectories were identified. Compared to the low-stable group, the adjusted ALM/BMI difference was -0.041 (95% CI: -0.060 to -0.022) and -0.114 (-0.141 to -0.086) in men, and -0.052 (-0.065 to -0.039) and -0.043 (-0.063 to -0.023) in women, respectively, for the medium-increase and high-increase groups. Further adjusting for the treadmill test duration attenuated these estimates to -0.022 (-0.040 to -0.004) and -0.061 (-0.089 to -0.034) in men and -0.026 (-0.038 to -0.014) and -0.007 (-0.026 to 0.012) in women. Compared to the low-stable insulin resistance trajectory between early and middle adulthood, the high-increase trajectory was associated with lower ALM/BMI in middle-aged men, but not women, without diabetes, after adjusting for cardiorespiratory fitness.