Mares and geldings in good body condition selected for hyperleptinemia vs. normal leptin concentrations were studied to determine whether the hyperleptinemic condition affected various characteristics of the hematologic and hormonal systems after a challenge with lipopolysaccharide endotoxin. Four mares and 4 geldings that were determined to be hyperleptinemic (mean plasma leptin concentrations of 10.0 to 15.5 ng/mL) and 4 mares and 4 geldings with mean plasma leptin concentrations between 2.4 and 5.5 ng/mL were administered Escherichia coli O55:B5 endotoxin (35 ng/kg of BW in 500 mL of saline over a 30-min infusion), or saline only, in pairs in a single-switchback design, with horses and treatments randomly assigned for the first infusion. Physiological variables and blood components were monitored for 24 h after the onset of infusions. Treatments were switched and the second infusions were administered 8 d later. Relative to vehicle infusion, endotoxin infusion increased (P < 0.01) the rectal temperature, heart rate, respiration rate, plasma total protein concentration, and blood packed cell volume; there was an interaction of leptin status, endotoxin treatment, and time for heart rate (P = 0.039), respiration rate (P = 0.018), and plasma total protein concentration (P = 0.054). Blood concentrations of leukocytes, lymphocytes, and neutrophils all decreased (P < 0.001) after endotoxin infusion; there was an interaction (P = 0.0057) between sex and leptin status for blood platelet concentration. Plasma leptin concentrations increased (P = 0.013) after endotoxin infusion in both hyperleptinemic horses and those with reduced leptin concentrations. There were interactions (P < 0.037) of sex with endotoxin treatment and time for plasma concentrations of cortisol and prolactin, whereas plasma GH concentrations were affected (increased; P < 0.001) only by time after infusion. Given that the effects of hyperleptinemia were generally minor, it was concluded that the hyperleptinemic condition, and its associated type-2 diabetic symptoms, has a minimal impact on the components of the hematologic and hormonal systems studied.