This study examined whether muscle injury and the accompanying inflammatory responses alter thermoregulation during subsequent exercise-heat stress. Sixteen subjects performed 50 min of treadmill exercise (45-50% maximal O₂ consumption) in a hot room (40°C, 20% relative humidity) before and at select times after eccentric upper body (UBE) and/or eccentric lower body (LBE) exercise. In experiment 1, eight subjects performed treadmill exercise before and 6, 25, and 30 h after UBE and then 6, 25, and 30 h after LBE. In experiment 2, eight subjects performed treadmill exercise before and 2, 7, and 26 h after LBE only. UBE and LBE produced marked soreness and significantly elevated creatine kinase levels (P < 0.05), but only LBE increased (P < 0.05) interleukin-6 levels. In experiment 1, core temperatures before and during exercise-heat stress were similar for control and after UBE, but some evidence for higher core temperatures was found after LBE. In experiment 2, core temperatures during exercise-heat stress were 0.2-0.3°C (P < 0.05) above control values at 2 and 7 h after LBE. The added thermal strain after LBE (P < 0.05) was associated with higher metabolic rate (r = 0.70 and 0.68 at 2 and 6-7 h, respectively) but was not related (P > 0.05) to muscle soreness (r = 0.47 at 6-7 h), plasma interleukin-6 (r = 0.35 at 6-7 h), or peak creatine kinase levels (r = 0.22). Local sweating responses (threshold core temperature and slope) were not altered by UBE or LBE. The results suggest that profuse muscle injury can increase body core temperature during exercise-heat stress and that the added heat storage cannot be attributed solely to increased heat production.