Interleukin (IL)-6 induces lipolysis when administered to humans. Consequently, it has been hypothesized that IL-6 is released from skeletal muscle during exercise to act in a hormone-like manner and increase lipolysis from adipose tissue to supply the muscle with substrate. In the present study, we hypothesized that suppressing lipolysis, and subsequent free fatty acid (FFA) availability, would result in a compensatory elevation in circulating IL-6 at rest and during exercise. Firstly, we had five healthy males ingest nicotinic acid at rest[NA; 10 mg.kg^-1 bm (initial dose), 5 mg.kg^-1 bm) (subsequent doses)]. Plasma was collected and analyzed for FFA and IL-6. After 120 min, plasma free fatty acid concentration was attenuated (0 min: 0.26 ± 0.05; 120 min: 0.09 ± 0.02 mmol.L^-1; P<0.01) while plasma IL-6 was concomitantly increased ~8 fold (0 min: 0.75 ± 0.18; 120 min: 6.05 ± 0.89 pg.mL^-1; P< 0.001). To assess the effect of lipolytic suppression on the exercise-induced IL-6 response, seven active, but not specifically trained, men performed two experimental exercise trials with (NA) or without (CON) nicotinic acid ingestion 60 min before (10 mg.kg^-1 bm) and throughout (5 mg.kg^-1 bm every 30 min) exercise. Blood samples were obtained before ingestion, 60 min after ingestion and throughout 180 min of cycling exercise at 62 ± 5 % of maximal oxygen consumption. IL-6 gene expression in muscle and adipose tissue sampled at 0, 90, and 180 min, was determined using semi-quantitative real-time PCR. IL-6 mRNA increased in CON (rest vs. 180 min; P<0.01) ~13-fold in muscle and ~42-fold in fat with exercise. NA increased (rest vs. 180 min; P<0.01) IL-6 mRNA 34-fold in muscle (CON vs. NA P=0.1) but the treatment effect was not statistically significant and 235-fold in fat (CON vs. NA P<0.01). Consistent with the study at rest, NA completely suppressed plasma FFA (180 min: CON 1.42 ± 0.07; NA 0.10 ± 0.01 mmol.L^-1; P<0.001) and increased plasma IL-6 (180 min: CON 9.81 ± 0.98; NA 19.23 ± 2.50 pg.mL^-1; P<0.05) during exercise. In conclusion, these data demonstrate that circulating IL-6 is markedly elevated at rest and during prolonged moderate-intensity exercise when lipolysis is suppressed.