Objective Associations of IRS1 genetic variation with adiposity and metabolic profile in U.S. Hispanic/Latino individuals of diverse backgrounds were examined. Methods Previously genome‐wide association study‐identified IRS1 variants (rs2943650, rs2972146, rs2943641, and rs2943634) as related to body fat percentage (BF%) and multiple metabolic traits were tested among up to 12,730 adults (5,232 men; 7,515 women) from the Hispanic Community Health Study/Study of Latinos. Results The C‐allele (frequency = 26%) of rs2943650 was significantly associated with higher BF% overall ( β = 0.34 ± 0.11% per allele; P  = 0.002) and in women ( β = 0.41 ± 0.14% per C‐allele; P  = 0.003), but not in men ( β = 0.28 ± 0.18% per C‐allele; P  = 0.11), though there was no significant sex difference. Using the inverse normal‐transformed data to compare effect sizes, it was found that the association with BF% was stronger in Hispanic/Latino women than that previously reported in European women ( β = 0.054 ± 0.018SD vs. β = 0.008 ± 0.011SD per C‐allele; P  = 0.03). The BF%‐increasing allele of rs2943650 was significantly associated with lower levels of fasting insulin, homeostatic model assessment of insulin resistance, hemoglobin A1c, and triglycerides and higher high‐density lipoprotein cholesterol ( P  < 0.05). Conclusions This study confirmed and extended previous findings of IRS1 variation associated with increased adiposity but a favorable metabolic profile in U.S. Hispanics/Latinos, with a relatively stronger genetic effect on BF% in Hispanic/Latino women compared with European women.