The objective of this study was to assess the effects of ration nutrient density on the energy balance and inflammatory response of dairy cows during and following dry-off. Forty-eight Holstein dairy cows (1.7 ± 0.9 lactations) were dried-off over a 5-d period, approximately 60 d before their expected calving dates. At the start of dry-off (d 1), cows were randomly assigned to either 1 of 2 TMR: control diet (1.48 Mcal/kg, 13.3% CP and 32.0% NFC) and treatment diet (1.44 Mcal/kg, 12.6% CP and 29.7% NFC), which was diluted with extra straw. During dry-off, cows were milked 1x/d on d 1, 2, 3 and a final time on d 5. Before the start of dry-off, cows were producing 26 ± 5.5 kg/d, milking 2x/d, and consuming a TMR (1.65 Mcal/kg, 16.1% CP and 41.7% NFC). Blood samples were collected from the coccygeal vein on d 1, 5, 7, 13, 19 and 25, and analyzed to determine serum concentrations of NEFA, glucose, and haptoglobin. Data were summarized by cow and day and analyzed in a repeated measures linear mixed-effect regression model. From d 5 to 25, NEFA concentrations were lower (P < 0.009) than at d 1 for both treatments. Cows fed the diluted ration tended to have lower NEFA on d 5 (0.08 vs 0.10 mmol/L; P = 0.09) and d 7 (0.07 vs 0.09 mmol/L; P = 0.06) than cows fed the control ration. Higher BW at dry-off was associated (P = 0.02) with lower NEFA concentration. Although there was no effect of treatment, glucose was elevated (P < 0.02) from d 5 to 19 in relation to d 1 and 25. Relative to d 1 (0.20 g/L), cows experienced elevated haptoglobin on d 7 (0.29 g/L; P = 0.005) and d 13 (0.38 g/L; P = 0.006). Cows fed the diluted ration had higher haptoglobin (0.37 vs 0.25 g/L; P = 0.04) on d 19 than did cows fed the control ration. Milk yield at the final milking before dry-off tended to be positively associated (P = 0.09) with greater haptoglobin during and after dry-off. These results suggest energy balance and inflammatory response of dairy cows during and after dry-off may be altered by controlling cow body weight, milk yield, and the magnitude change, from lactation to the dry period, in nutrient density of the ration consumed.