The effects of monensin on the energy metabolism of dairy cows in early lactation were investigated in a large clinical trial that was randomized and double-blinded. A total of 1010 Holstein cows and first lactation heifers were allocated to receive a controlled-release capsule of monensin or a placebo at 3 wk prior to expected calving date. Treatments were randomized across 25 dairy farms located near Guelph, Ontario, Canada. Serum samples obtained at the time of treatment administration and at wk 1, 2, 3, 6, and 9 postcalving were analyzed for beta-hydroxybutyrate, glucose, aspartate aminotransferase, urea, total protein, calcium, and phosphorus. Cows were also assigned a body condition score at the time each sample was obtained. Monensin treatment significantly reduced serum beta-hydroxy-butyrate concentrations at wk 1, 2, and 3 postpartum and significantly raised serum glucose concentrations during wk 1 and 2 of lactation. In addition, monensin treatment significantly reduced the loss of body condition score and decreased serum activity of aspartate aminotransferase during the postpartum period. Concentrations of serum urea were significantly higher during wk 2 and 3 postpartum for the cows that were treated with monensin. Monensin treatment had no effect on the concentrations of calcium, phosphorus, or total protein.