The objective of this study was to evaluate alterations in blood variables related to innate immunity, carbohydrate and lipid metabolism in transition dairy cows with ketosis. Multiparous Holstein dairy cows (n = 100) were involved in the study. Five blood samples were collected from the coccygeal vein during the −8 to +8 wk around parturition, once per week before the morning feeding. Serum samples collected at −8, −4, time of diagnosis of disease, +4 and +8 wk relative to parturition from 6 healthy control cows (CON) and 6 cows with ketosis were selected for analyzes. Samples were analyzed for β-hydroxybutyrate (BHBA), lactate, nonesterified fatty acids (NEFA), interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), haptoglobin (Hp), and serum amyloid A (SAA). Health status, feed intake, and milk yield data were monitored for each cow during the whole experimental period. Data were processed statistically by MIXED procedure of SAS 9.2. Results revealed that cows with ketosis had greater concentrations of serum BHBA (1,014 vs 504 ± 140 μmol/L, P = 0.04), lactate (4,236 vs 2,240 ± 351 μmol/L, P < 0.01), IL-6 (255 vs 27 ± 55 pg/mL, P = 0.03), TNF (0.47 vs 0.19 ± 0.07 ng/mL, P = 0.03), and SAA (24,107 vs 8,550 ± 3,457 μg/mL, P = 0.01) in comparison with the CON animals. Enhanced serum concentrations of BHBA (483 vs 312 ± 19 μmol/L at −4 wk, P = 0.02), lactate (5,795 vs 2,455 ± 349 μmol/L at −8 wk, P = 0.01; and 4,478 vs 2,162 ± 185 μmol/L at −4 wk, P = 0.01), IL-6 (183 vs 19 ± 6 pg/mL at −8 wk, P < 0.01; and 330 vs. 48 ± 18 pg/mL at −4 wk, P < 0.01) and TNF (0.64 vs 0.27 ± 0.05 ng/mL at −4 wk, P = 0.03) at −4 or −8 wks before parturition were identified in cows with ketosis compared with the CON group. Cows with ketosis also had overall lower feed intake (35.70 vs 39.81 ± 1.74 kg/d, P = 0.03) and milk production (32.25 vs 42.16 ± 2.53 kg/d, P < 0.05) vs CON animals. Overall results indicate that cows affected by ketosis displayed an activated innate immunity and altered carbohydrate and lipid metabolism several weeks before diagnosis of disease. More research is warranted to better understand the agent(s) that contribute(s) to ketosis in transition dairy cows and to validate utilization of these blood variables to predict disease state in cows.