Background: Obesity is associated with major changes in the circulating IGF system. However, it is not clear to what extent the IGF system is normalized following diet, and the possible role of different types of diet is also unknown. Objective: To compare changes in the circulating IGF system following 12 weeks of moderate energy restriction (7000 kJ/day) in overweight or obese males on a high protein high red meat diet (HP) or a high carbohydrate diet (HC). Design: Seventy-six men (mean age, 51±1.0 years; body mass index, 32.8±0.5 kg/m2) were allocated to matched groups treated with isocaloric diets of HP (n=34) or HC (n=42). Outcome measures were weight, body composition, IGF-related peptides, homoeostasis model assessment of insulin resistance (HOMA1-IR) and adipokines. Results: Weight loss did not differ between diets (HP 8.5±0.6 kg; HC 8.2±0.6 kg, P>0.05). IGF-related peptides increased total IGF1 (HP 23%; HC 18%, P<0.0001), bioactive IGF1 (HP 18%; HC 15%, P<0.002), IGF1:IGF-binding protein-3 (IGFBP-3; HP 29%; HC 22%, P<0.0001) and IGFBP-1 (HP 24%; HC 25%, P<0.01). By contrast, decreases were observed in IGFBP-3 (HP - 4%; HC - 3%, P<0.01), pro-IGF2 (HP - 3%; HC - 6%, P=0.001), total IGF2 (HP - 7%; HC - 3%, P=0.001) and sIGF2R (HP - 10%; HC - 6%, P<0.005). Only IGFBP-2 increased differentially by diet (HP 34%; HC 50%, P<0.0001, diet P<0.05). Adiponectin increased in both diets, but leptin and HOMA-IR decreased (P<0.001). Conclusions: Weight loss induced by moderate energy restriction modulated the IGF system independent of dietary protein or red meat content. The effect of diet on IGFBP-2 appeared to have limited biological effect as total IGF2 and pro-IGF2 did not change.