Lipid metabolism was studied in 21 horses with hyperadrenocorticism. To be included in the study, horses had to have histologic evidence of a pars intermedia adenoma found at necropsy (n = 9), a baseline ACTH concentration greater than 400 pg/ml (n = 6), or a plasma cortisol concentration 2 hours after i.v. administration of 25 IU of ACTH greater than 413 nmol/L (n = 16). Mean +/- SD baseline plasma cortisol concentration was 338 +/- 261 nmol/L (n = 20), mean +/- SD plasma insulin concentration was 97 +/- 54 microU/ml (n = 15), mean +/- SD plasma beta-hydroxybutyrate concentration was 1.8 +/- 1.2 mg/dl (n = 21), and mean +/- SD plasma nonesterified fatty acids concentration was 6.2 +/- 6.4 mg/dl (n = 21). None of the horses had hyperlipemia. Compared with clinically normal horses, horses with hyperadrenocorticism had increased lipolysis and increased ketogenesis. It was concluded that cortisol cannot be the sole factor contributing to insulin resistance in horses with hyperadrenocorticism.