OBJECTIVE - Although cumulative evidence suggests that increased oxidative stress may lead to insulin resistance in vivo or in vitro, community-based studies are scarce. This study examined the longitudinal relationships of oxidative stress biomarkers with the development of insulin resistance and whether these relationships were independent of obesity in nondiabetic young adults. RESEARCH DESIGN AND METHODS - Biomarkers of oxidative stress (F 2-isoprostanes [F2Isop] and oxidized LDL [oxLDL]), insulin resistance (the homeostasis model assessment of insulin resistance [HOMA-IR]), and various fatness measures (BMI, waist circumference, and estimated percent fat) were obtained in a population-based observational study (Coronary Artery Risk Development in Young Adults) and its ancillary study (Young Adult Longitudinal Trends in Antioxidants) during 2000-2006. RESULTS - There were substantial increases in estimated mean HOMA-IR over time. OxLDL and F 2Isop showed little association with each other. Mean evolving HOMA-IR increased with increasing levels of oxidative stress markers (P < 0.001 for oxLDL and P = 0.06 for F2Isop), measured in 2000-2001. After additional adjustment for adiposity, a positive association between oxLDL and HOMA-IR was strongly evident, whereas the association between F 2Isop and HOMA-IR was not. CONCLUSIONS - We observed positive associations between each of two oxidative stress markers and insulin resistance. The association with oxidized LDL was independent of obesity, but that with F2Isop was not. © 2009 by the American Diabetes Association.