Introduction: The pro-inflammatory cytokine interleukin-6 (IL-6) may modulate the onset/progression of complications of diabetes. As this cytokine increases after exercise, and many other exercise responses are altered by prior glycemic fluctuations, we hypothesized that prior hyperglycemia may exacerbate the IL-6 response to exercise. Methods: Twenty children with Type 1 diabetes (T1DM) (12m/8f, age 12-15 years) performed 29 exercise studies (30 min intermittent cycling at ~80% peak VO2). Children were divided in 4 groups based on highest morning glycemic reading (BG<150, BG151-200, BG201-300 or BG>300 mg/dl). All exercise studies were performed in the late morning, after hyperglycemia had been corrected and steady state conditions (plasma glucose <120 mg/dl, basal insulin infusion) had been maintained for at least 90 min. Blood samples for IL-6, growth factors and counterregulatory hormones were drawn at pre-, end-, and 30 min post-exercise time points. Results: At all time points, circulating IL-6 was lowest in BG<150, and progressively higher in the other three groups. The exercise-induced increment also followed a similar dose-response pattern (BG<150, 0.6±0.2 ng/ml; BG151-200, 1.2±0.8 ng/ml; BG201-300, 2.1±1.1 ng/ml; BG>300, 3.2±1.4 ng/ml). Other measured variables (GH, IGF-I, glucagon, epinephrine, cortisol) were not influenced by prior hyperglycemia. Conclusion: Recent prior hyperglycemia markedly influenced baseline and exercise-induced levels of IL-6 in a group of peri-pubertal children with T1DM. While exercise is widely encouraged and indeed often considered part of diabetic management, our data underscore the necessity to completely understand all adaptive mechanisms associated with physical activity, particularly in the context of the developing diabetic child.