Objective-To use threshold concentrations of acetone and beta-hydroxybutyrate in milk and serum, respectively; identify risk for ketosis and endometritis; and assess analyses of blood and milk samples as predictors of risk for ketosis in high-yielding dairy cows. Animals-90 multiparous Holstein cows. Procedure-At intervals before and after parturition, blood samples were obtained for determination of glucose, nonesterified fatty acids, leptin, insulin, insulin-like growth factor-1, and beta-hydroxybutyrate concentrations. Samples of milk were obtained at similar intervals after parturition for determination of fat content and concentrations of acetone, protein, and lactose. Reproductive examination of each cow was performed weekly. Results-For each cow, threshold concentrations of acetone and β-hydroxybutyrate were calculated as 75th and 90th percentiles of maximum postpartum concentrations of acetone in milk (0.40 and 0.87 mmol/L) and β-hydroxybutyrate in serum (2.30 and 3.51 mmol/L). Significant decrease in milk production (442 to 654 kg of energy-corrected milk/305-day period per cow) was associated with acetone or beta-hydroxybutyrate in excess of threshold values. Milk acetone concentrations > 0.40 mmol/L were associated with 3.2 times higher risk for endometritis. Low plasma glucose, high serum beta-hydroxybutyrate, and high milk acetone concentrations during week 1 after parturition were indicators of increased risk for ketosis later during lactation. Conclusions and Clinical Relevance-Determination of milk acetone concentration during the week after parturition may identify cows at risk for ketosis and endometritis; with appropriate interventions, development of disease and production losses may be reduced.