Epidemiological studies show that increased insulin-like growth factor (IGF)-I concentrations are related to increased colorectal cancer risk. A reduced colorectal cancer risk has been associated with isoflavones, which might affect the IGF-system because of their weak estrogenic activity. We conducted a randomized, placebo-controlled, double-blind crossover study to investigate the effect of an 8-wk isolated isoflavone supplementation (84 mg/d) on serum concentrations of total IGF-I, free IGF-I, total IGF-II, IGF binding protein (BP)-1, IGFBP-2, and IGFBP-3. Additionally, we investigated whether IGF-system component differences were related to concentrations of the more potent estrogenic isoflavone metabolite, equol. Our study population consisted of 37 men with a family history of colorectal cancer or a personal history of colorectal adenomas. Isoflavone supplementation did not significantly affect serum total IGF-I concentrations (relative difference between serum total IGF-I concentrations after isoflavone supplementation and after placebo: -1.3%, 95% CI -8.6 to 6.0%). Neither free IGF-I, nor total IGF-II, IGFBP-1, IGFBP-2, or IGFBP-3 concentrations were significantly altered. Interestingly, the change in serum IGF-I concentrations after isoflavone supplementation was negatively associated with serum equol concentrations (r=-0.49, P=0.002). In conclusion, isolated isoflavones did not affect the circulating IGF-system in a male high-risk population for colorectal cancer. However, to our knowledge, this is the first study that suggests isoflavones might have an IGF-I lowering effect in equol producers only. This underlines the importance of taking into account equol status in future isoflavone intervention studies.