The objective of this study was to investigate the longitudinal relation between the insulin-like growth factor I (IGF-I)/IGF-binding protein (IGFBP) system and cognitive function. The study population consisted of a sample of 186 healthy participants from the population-based Rotterdam Study, aged 55-80 yr. At baseline, we determined fasting blood levels of free and total IGF-I, IGFBP-1, and IGFBP-3. The 30-point Mini-Mental State Examination (MMSE) was used to assess cognitive impairment at baseline (MMSE score of <26; 6% of the sample) and cognitive decline after, on the average, 1.9 yr of follow-up (drop in MMSE score of >1 point/year; 22% of the sample). Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression, with adjustment for age, sex, education, body mass index, and fasting insulin levels. Total IGF-I appeared to be inversely related to cognitive impairment, although not significantly. Higher total IGF-I and the total IGF-I/IGFBP-3 ratio were associated with less cognitive decline (OR per SD increase = 0.65; 95% CI = 0.44-0.95 and OR = 0.59; 95% CI = 0.39-0.87, respectively). No relation was observed between free IGF-I and cognitive decline (OR = 0.99; 95% CI = 0.68-1.44). In conclusion, in this prospective study higher serum total IGF-I levels and higher total IGF-I/IGFBP-3 ratios, but not higher free IGF-I levels, were associated with less cognitive decline over the following 2 yr. Circulating total IGF-I levels may reflect an underlying biological process that influences cognitive decline.