Inflammatory related blood metabolites are key indicators of stress that dairy cows can experience during the transition period. The objective of this study was to determine the effects of feeding a fully acidified dietary cation-anion difference (DCAD) diet prepartum to Holstein cows (n = 76) at 2 different concentrations of dietary Ca on circulating inflammatory related blood metabolites both pre- and postpartum. Multiparous Holstein cows were enrolled 50d before expected calving and followed until 75 DIM. Treatments began 28d before expected calving and were CON (n = 23), a positive DCAD diet with low dietary Ca (0.4% DM); LOW (n = 22), a fully acidified DCAD diet (urine pH = 5.7); HIGH (n = 25), a fully acidified DCAD diet (urine pH = 5.7) with high dietary Ca (2.0% DM). Plasma lipopolysaccharide binding protein (LBP) and plasma serum amyloid A (SAA) were assessed at −30, −21, −7, 15, and 30 d relative to calving using commercially available kits. Data were analyzed using PROC MIXED in SAS (v9.4). Contrasts included CONT1 (CON vs. the average of LOW and HIGH) and CONT2 (LOW vs. HIGH). Prepartum LBP and SAA concentrations increased for all treatments as cows approached calving (P < 0.001 and P < 0.001, respectively). Prepartum concentrations of LBP and SAA were 5.21, 5.01, 8.65 ± 0.47 µg/mL, and 20.28, 31.18, 41.11 ± 0.9 µg/mL for d −30, −21, and −7, respectively. Cows fed LOW had a higher LBP concentration prepartum than cows fed HIGH (7.33 vs. 5.84 ± 0.47 µg/mL, respectively; P = 0.03). Postpartum LBP and SAA concentrations decreased for all treatments over time (P = 0.006 and P = 0.02, respectively). Postpartum concentrations of LBP and SAA were 9.09, 7.76 ± 0.37 µg/mL, and 37.49, 34.57 ± 0.82 µg/mL for d 15, and 30, respectively. In conclusion, cows in HIGH had a lower circulating LBP concentration than cows in LOW prepartum. However, postpartum LBP, and both pre- and postpartum SAA concentrations were not statistically different in both CONT1 and CONT2. Cows in all treatments follow a general increase of LBP and SAA concentrations approaching calving and a decrease of LBP and SAA concentrations postpartum.