Changes in insulin‐like growth factor‐I (IGF‐I) and insulin‐like growth factor binding proteins (IGFBPs) were correlated with protein synthesis and breakdown using [1‐ 13C]leucine before chemotherapy and during subsequent febrile neutropenia (FN) in eight children with cancer, aged 6.3–17.5 y. IGF‐I levels were similar to age‐matched controls before chemotherapy (mean ±SEM: 250 ±28 and 228 ±22 μg l‐1, respectively). During FN, IGF‐I fell to 156 ±22 /ng l ‐1(p= 0:02), and rose to 276 ±27 μ g l ‐1 with recovery at 6 months (p = 0:004). Similarly, IGFBP‐3 decreased from 4.0 ±0.2mgl‐1 before chemotherapy to 3.0 ±0.3 mgl‐1 during FN (p= 0:01), and returned to 4.1 ±0.2mgl ‐1 at 6 months (p= 0:01). IGF‐I correlated with IGFBP‐3 (r=+0:7, p <0:001). Scanning densitometry showed a decrease in IGFBP‐3 from 94 to 54% during FN, when the presence of IGFBP‐3 protease activity was observed. Compared with normal human serum, IGFBP‐2 was elevated throughout the study. IGFBP‐1 increased from 14.6 ±3.5 to 30.6 ±2.8/ngl‐1 (p = 0:004), whereas serum insulin decreased from 26.5 ±6.8 to 7.8 ±0.8 mUl‐1 (p= 0:03) before and during FN, respectively. Whilst IGF‐I and IGFBP‐3 fell, daytime growth hormone increased from 3.3 ±0.6 to 6.7±0.8mUl ‐1 (p= 0:01), and cortisol from 197 ±48 to 594±98nmoll ‐1 (p = 0:005). Albumin decreased from 47 ±2 to 38 ±2gl‐1 (p= 0:004) and improved to 47 ±2gl‐1 with recovery (p= 0:003). Protein synthesis increased from 4.5 ±0.4 to 5.0 ±0.6gkg‐1 d‐1 before chemotherapy and during FN, while protein breakdown rose from 5.4 ±0.4 to 6.3 ±0.4kg‐1d‐1. Increasing protein breakdown was related to falling IGF‐I and IGFBP‐3 levels. Modification of IGFBP‐3 by circulating proteolytic activity may alter IGF bioavailability, allowing protein synthesis to increase during periods of severe catabolic stress.