We examined whether a systemic marker of oxidative stress, F(2)-isoprostanes (F(2)-IPs), was associated with total and regional adiposity, adipocytokines, and change in adiposity. Using data from 726 participants enrolled in the Health, Aging, and Body Composition (Health ABC) study, F(2)-IPs and adipocytokines were measured from baseline plasma samples. Total adiposity was measured by whole-body dual-energy X-ray absorptiometry and regional adiposity by abdominal and thigh computed tomography scans at baseline and 5-year follow-up. ANOVA models were estimated to examine associations between F(2)-IP tertiles and baseline adiposity and changes in body composition. Median F(2)-IPs was 54.3 pg/ml; women had significantly higher levels than men (61.5 vs. 48.9 pg/ml, P < 0.001). F(2)-IPs were associated with higher levels of adiponectin, leptin, and tumor necrosis factor-α (TNF-α). Positive associations were found between F(2)-IPs and all measures of total and regional adiposity among women. In linear regression models, adipocytokines mediated associations among women. Over 5 years of follow-up, women in the highest vs. lowest F(2)-IP tertile exhibited significant loss of weight (lowest tertile: -1.1 kg, highest tertile: -2.7 kg, P < 0.05). In conclusion, F(2)-IPs were associated with measures of total and regional adiposity in women alone and these associations were partially explained by adipocytokines. F(2)-IPs predicted loss of total adiposity over time among women.