The purpose of the present investigation was to examine the effect of exercise-induced muscle injury on hemodynamic responses during exercise. Ten subjects performed unilateral isometric knee extensions (IKE) at 30% of preinjury maximum voluntary contraction to fatigue and for 3 min before and 48 h after muscle injury. Muscle injury was elicited by performing 8 sets of 10 repetitions of eccentric muscle actions of the knee extensor muscles (i.e., quadriceps muscles) by lowering a weight equivalent to 75% of eccentric maximum load. Exercise time to fatigue for IKE at 30% of maximum voluntary contraction in the injured leg was significantly decreased from preinjury to postinjury IKE (257 ± 21 to 203 ± 23 s; n = 10), but was unchanged in the control leg (244 ± 16 to 254 ± 20 s; n = 7). With the use of a 10-cm visual analog scale, ratings of muscle soreness in the injured leg increased from 0 to 5.1 ± 0.7 cm (P < 0.001) but were not changed in the control leg (0 both times). Both heart rate and mean arterial pressure responses to exercise were unchanged following muscle injury. Forearm blood flow and forearm vascular resistance were not different at rest and during the first minute of exercise before and after muscle injury. However, after muscle injury, forearm blood flow was significantly lower and forearm vascular resistance was significantly higher (P < 0.03) during the second and third minutes of exercise. There were no significant changes in any variables with the contralateral control leg. In four subjects, resting magnetic resonance images demonstrated a 23% greater relative cross-sectional area of the knee extensor muscles with an elevated transverse relaxation time in the injured versus control leg. The results indicate that forearm vascular resistance is augmented during isometric knee extension following muscle injury of the knee extensor muscles. The data suggest that muscle injury alters vascular control to non-exercising skeletal muscle during exercise.