The objective of this study was to examine the relationship between the interleukin-6 (IL-6) -174 G>C promoter polymorphism and exercise-induced femoral cortical bone resorption. Skeletal response to exercise was assessed in 130 male Caucasian army recruits. Five cross-sectional magnetic resonance images of the right femur were obtained before and after a 10-week period of basic physical training, and changes in cross-sectional cortical area were calculated. Recruits were genotyped for the -174 G>C IL-6 promoter polymorphism. Genotype frequencies (GG 36%, GC 47%, CC 22.17%) were in Hardy-Weinberg equilibrium. The mean percentage change in proximal femoral cross-sectional cortical area was strongly IL-6 genotype-dependent, with GG homozygotes losing 6.8 (3.82)% in cortical area, GC gaining+5.5 (4.88)% and CC gaining+17.3 (9.46)% (P=0.007 for linear trend). These changes persisted throughout the right femur and were significant in the femur as a whole (P=0.03). This study demonstrates an association between a functional polymorphism in the IL-6 gene and femoral cortical remodelling during strenuous physical exercise. Previous studies have suggested an important role for IL-6 in the regulation of bone mass in postmenopausal women, and in the invasion of bone by metastatic tumour deposits. These data extend these observations to the regulation of bone mass in healthy males, supporting a fundamental role for IL-6 in the regulation of bone mass and bone remodelling in humans.