It remains unclear whether the acute inflammatory response that follows muscle damaging exercise (e.g. increase in circulating pyrogen interleukin (IL)-6), increases heat storage during subsequent exercise-heat stress, as proposed by Montain et al. (2000). As such, we tested the hypothesis that acute inflammation following exercise-induced muscle-damage (EIMD), using a downhill running model, increases core temperature during subsequent endurance exercise in the heat. With informed consent, thirteen non-heat-acclimated healthy males (mean age ± SD, 20 ± 2 years) completed two, randomised and counterbalanced treadmill running trials separated by two-weeks. Participants performed a treatment which involved running for 60 min at 64%VO2max in 20°C, 40% relative humidity (RH); on one occasion on a -10% gradient (EIMD), and another on a +1% gradient (CON). Following both treatments, participants rested for 30 min, timed to coincide with elevated circulating inflammatory mediators, and then performed an exercise heat-stress test (HS) which involved running for 40 min at 65% VO2max on a +1% gradient in 33°C, 50% RH. Rectal core temperature (Tre) and oxygen uptake (VO2) were measured throughout HS. Plasma IL-6 concentration was assessed prior to treatment (baseline), and immediately pre and post HS. Data were analysed using ANOVA, paired t-tests and Pearson’s correlations. Plasma IL-6 concentration demonstrated a significant interaction (P < 0.001). There was no baseline difference between trials, but plasma IL-6 concentration was significantly greater on EIMD than CON immediately pre (P < 0.05), and post HS (P < 0.01, Fig. 1A). Despite similar Tre prior to HS (EIMD 37.8 ± 0.2, CON 37.6 ± 0.2°C, P > 0.05), ΔTre was significantly greater during HS on EIMD (P < 0.01, Fig. 1B) resulting in a higher final Tre on EIMD (EIMD 39.5 ± 0.4, CON 39.0 ± 0.4°C, P < 0.01). The acute inflammatory response after treatment, measured as the difference in plasma IL-6 response between EIMD and CON, correlated well with the difference between trials in the ΔTre during HS (r = 0.58, P < 0.05), and with the final Tre during HS (r = 0.67, P < 0.05). Mean VO2 during HS was significantly greater on EIMD (3.0 ± 0.3 L/min) than CON (2.8 ± 0.3 L/min, P < 0.01). Despite this decreased economy, the difference in VO2 between EIMD and CON did not correlate well with the difference between trials in the ΔTre during HS (r = 0.24, P = 0.43) or the final Tre during HS (r = 0.40, P = 0.17). These data show that a bout of downhill running increases the short-term plasma IL-6 response to exercise and that this increase is associated with elevated Tre during subsequent endurance exercise in the heat. These results have practical relevance for athletes and soldiers undertaking multiple bouts of heavy exercise with an eccentric component in the heat.