The geriatric syndrome of frailty has been conceptualized as a loss of physiologic reserve associated with endocrine dysregulation and immune dysfunction. Our prior studies suggest that the frailty syndrome is associated with elevated serum IL-6 levels. In the present study, our aim is to evaluate the possible role of endocrine dysregulation and its relationship with serum IL-6 in the pathogenesis of this syndrome. Using a recently validated screening algorithm for frailty, we identified 18 frail and 33 non-frail community-dwelling older adults for inclusion in this study. Serum levels of insulin-like growth factor-I (IGF-I), DHEA-S, and IL-6 were measured by immunoassays. The inter-relationships among serum levels of IL-6, DHEA-S, and IGF-I were determined by linear regression analysis. Age-adjusted serum levels of IGF-I (88+/-49 vs 122+/-47 [ng/mL], p<0.023) and DHEA-S (0.30+/-0.21 vs 0.53+/-0.25 [microg/mL], p=0.016) were significantly lower in frail vs non-frail individuals, respectively. There was a trend for IL-6 to be inversely correlated with IGF-I in the frail (r=-0.42; p=0.082) but not the non-frail group (r=0.12, p=0.521). Frail subjects have lower levels of serum IGF-I and DHEA-S and higher levels of IL-6 than do non-frail, age-matched individuals. The trend toward an inverse correlation between IGF-I and IL-6 in the frail, but not the non-frail group, suggests potential interaction between endocrine and immune/cytokine dysregulation that requires further study in larger cohorts.