This study determined whether disrupted glucose and insulin responses to an oral glucose-tolerance test (OGTT) induced by eccentric exercise were attenuated after a repeated bout. Female participants (n = 10, age 24.7 +/- 3.0 yr, body mass 64.9 +/- 7.4 kg, height 1.67 +/- 0.02 m, body fat 29% +/- 2%) performed 2 bouts of downhill running (DTR 1 and DTR 2) separated by 14 d. OGTTs were administered at baseline and 48 hr after DTR 1 and DTR 2. Maximum voluntary isometric quadriceps torque (MVC), subjective soreness (100-mm visual analog scale), and serum creatine kinase (CK) were assessed pre-, post-, and 48 hr post-DTR 1 and DTR 2. Insulin and glucose area under the curve (38% +/- 8% and 21% +/- 5% increase, respectively) and peak insulin (44.1 +/- 5.1 vs. 31.6 +/- 4.0 muU/ml) and glucose (6.5 +/- 0.4 vs. 5.5 +/- 0.4 mmol/L) were elevated after DTR 1, with no increase above baseline 48 hr after DTR 2. MVC remained reduced by 9% +/- 3% 48 hr after DTR 1, recovering back to baseline 48 hr after DTR 2. Soreness was elevated to a greater degree 48 hr after DTR 1 (48 +/- 6 vs. 13 +/- 3 mm), with a tendency for greater CK responses 48 hr after DTR 1 (813 +/- 365 vs. 163 +/- 43 U/L, p = .08). A novel bout of eccentric exercise confers protective effects, with subsequent bouts failing to elicit disruptions in glucose and insulin homeostasis.