OBJECTIVES: This study examined associations between well-being and serum levels of insulin-like growth factor 1 (IGF-I) and its primary binding protein IGFBP-3 in a large population-based study of older adults. Additionally, the influence of physical activity on the effect of hormone levels on positive mental health was examined. METHODS: Cross-sectional data from 985 participants of the KORA-Age study (age range 64-93) was used in sex-specific multivariable regression analyses to assess associations between both IGF-I and IGFBP-3 with well-being (World Health Organization (WHO) -5) or ill-being (geriatric depression scale (GDS) -15). Models were increasingly adjusted for age, leisure time physical activity, sleep patterns, BMI, smoking, and cognitive scores based on causal diagrams. Well-being and depression scales were standardized to facilitate comparisons of growth hormone effects. Adjusted means of the WHO-5 score were assessed for the interaction between quintile levels of IGF-I or IGFBP-3 with high or low levels of physical activity. RESULTS: Fully adjusted models demonstrated that increased IGFBP-3 was positively associated with the WHO-5 in women (β estimate=0.14, standard error (SE)=0.06) and less so in men (β=0.11, SE=0.07). IGF-I was positively associated with the GDS-15 depression scale (β=0.11, SE=0.06) and negatively associated with well-being (β=-0.11, SE=0.06) in women and similar but not statistically discernable effects were observed in men. Adjusted mean WHO-5 scores illustrated the positive effect of both physical activity and higher IGFBP-3 on well-being in women only. CONCLUSIONS: These data demonstrate opposite and independent associations of IGF-I and IGFBP-3 on well-being in women, and suggest a neuroprotective effect of IGFBP-3 in older age.