The pleiotropic cytokine interleukin-6 (IL-6) has been demonstrated to increase during exercise. Little is known regarding the response of the soluble IL-6 receptors (sIL-6R and sgp130) during such exercise. The aim of the current study was to investigate the response of plasma IL-6, sIL-6R and sgp130 during fatiguing submaximal exercise in humans. Twelve participants underwent an incremental exercise test to exhaustion and one week later performed a submaximal exercise bout (96 ± 6% lactate threshold) to volitional exhaustion. Blood samples taken at rest and immediately post exercise were analyzed for IL-6, sIL-6R and sgp130. IL-6 increased (P < 0.01) by 8.4 ± 8.9 pg ml⁻¹ (75.7%) during the exercise period. sIL-6R and sgp130 also increased (P < 0.05) by 2.7 ± 3.9 ng ml⁻¹ (9.6%) and 37.7 ± 55.6 ng ml⁻¹ (9.6%), respectively. The current study is the first investigation to demonstrate that alongside IL-6, acute exercise stress results in an increase in both sIL-6R and sgp130.