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Observational studies show inverse associations between intake of whole grain and adiposity and cardiovascular risk; however, only a few dietary intervention trials have investigated the effect of whole-grain consumption on health outcomes. We studied the effect of replacing refined wheat (RW) with whole-grain wheat (WW) for 12 wk on body weight and composition after a 2-wk run-in period of consumption of RW-containing food intake. In this open-label randomized trial, 79 overweight or obese postmenopausal women were randomized to an energy-restricted diet (deficit of ~1250 kJ/d) with RW or WW foods providing 2 MJ/d. Body weight and composition, blood pressure, and concentration of circulating risk markers were measured at wk 0, 6, and 12. Fecal output and energy excretion were assessed during run-in and wk 12. Plasma alkylresorcinol analysis indicated good compliance with the intervention diets. Body weight decreased significantly from baseline in both the RW (-2.7 ± 1.9 kg) and WW (-3.6 ± 3.2 kg) groups, but the decreases did not differ between the groups (P = 0.11). The reduction in body fat percentage was greater in the WW group (-3.0%) than in the RW group (-2.1%) (P = 0.04). Serum total and LDL cholesterol increased by ~5% (P < 0.01) in the RW group but did not change in the WW group; hence, the changes differed between the groups (P = 0.02). In conclusion, consumption of whole-grain products resulted in a greater reduction in the percentage fat mass, whereas body weight changes did not differ between the RW and WW groups. Serum total and LDL cholesterol, two important risk factors of cardiovascular disease, increased with RW but not WW consumption, which may suggest a cardioprotective role for whole grain.