The objective of this study was to determine the effect of decreasing dietary cation-anion difference (DCAD) in the prepartum period on prepartum urine pH and peripartum plasma mineral concentrations. Multiparous Holstein cows (n = 89) were allocated randomly to one of 3 prepartum diets formulated with decreasing DCAD: CON (+17.5 mEq/100 g DM), MED (+3.6 mEq/100 g DM), or LOW (−10.9 mEq/100 g DM), beginning 24 d before expected parturition. Analyzed DCADs were +18.3, +5.9, and −7.4 mEq/100 g DM. Cows were fed a common postpartum diet from parturition until 63 d in milk (DIM). Blood was collected 1 × /wk prepartum, 2 × in 24 h postpartum, 1 × /d until 5 DIM, and 3 × /wk until 14 DIM. Repeated measures analyses were conducted using the MIXED procedure of SAS with linear and quadratic effects of decreasing prepartum DCAD as contrasts. There was a quadratic effect on urine pH (CON = 8.20, MED = 7.84, LOW = 5.98; P < 0.01). There tended to be an interaction between DCAD and parity (2nd lactation vs. 3rd and greater) for prepartum Mg (P = 0.08) such that Mg decreased with decreasing DCAD for older cows (P < 0.05) but not for 2nd lactation cows. Postpartum Ca increased linearly with decreasing DCAD (CON = 8.84, MED = 8.89, LOW = 9.19; P < 0.01) with greater increases through 5 DIM (DCAD × Day; P = 0.06). There tended to be an interaction between DCAD and parity (P = 0.06) such that Ca was increased more for older cows fed lower DCAD levels (CON = 8.68, MED = 8.63, LOW = 9.16; P < 0.01) than for 2nd lactation cows. Postpartum P tended to decrease linearly (P = 0.08). For 2 d postpartum cows fed LOW had lower Mg (DCAD × Day; P < 0.01). Incidence of hypocalcemia (HC, plasma Ca < 8.5 mg/dL) was significantly different at 1 DIM (P = 0.02). When parity groups were analyzed separately, incidence of HC in older cows was decreased by decreasing prepartum DCAD at 0.6 (P = 0.07), 1 and 2 DIM (P < 0.01) but did not differ for 2nd lactation cows. Decreasing prepartum DCAD improved Ca status, decreased incidence of HC, and had varied effects on other minerals over the periparturient period.