CONTEXT: Circulating insulin-like growth factors (IGFs) are bound in complexes which affect their tissue-accessibility. Interstitial fluid is in close proximity to target cells, but the IGF-system is not well-described herein. OBJECTIVE: To perform a thorough comparison of the IGF-system in suction blister fluid (SBF) vs. in serum, with emphasis on bioactive IGF levels. DESIGN: Eight hour study including samples collected in the fasting state (20h) and after a meal. SETTING: Clinical research facility. PARTICIPANTS: Six healthy males (age 37.0±8.8years, BMI 22.5±1.4kg/m(2)) (mean±SD). MAIN OUTCOME MEASURE: Serum and SBF concentrations of bioactive IGF (determined in vitro by specific IGF-I receptor (IGF-IR) phosphorylation assay), immunoreactive IGF and IGF binding protein (IGFBP) levels, Western ligand blotting (WLB) of IGFBPs and IGFBP-3 Western immunoblotting (WiB). RESULTS: The ability of SBF to phosphorylate the IGF-IR in vitro was 41±27% higher than that of serum (P=0.007 by repeated measures ANOVA). By contrast, immunoreactive IGF and IGFBP-concentrations were approximately 50% lower in SBF than in serum (all P≤0.002). A marked difference in the composition of IGFBPs between serum and SBF was observed, including 3-fold elevated amounts of IGFBP-3 fragments in SBF (P<0.001). For both IGF-I, IGF-II and IGFBP-2, the effect of food intake differed between serum and SBF (all P≤0.03). CONCLUSION: Despite lower concentrations, the in vitro IGF bioactivity was higher in SBF than in serum. This may relate to an increased enzymatic IGFBP-degradation and an altered IGFBP-composition in SBF, making more IGF-I and -II accessible to the IGF-IR. The impact of food intake on the IGF system differs between serum and interstitial fluid.