Thiazolidinediones (TZD) are potent synthetic ligands for peroxisome proliferator-activated receptor-gamma that have been shown previously to reduce plasma nonesterified fatty acids and increase peripartal dry matter intake (DMI) in dairy cows. Data from Holstein cows (n = 36) entering their second or greater lactation were used to determine whether late prepartum administration of TZD would affect periparturient metabolism, milk production, and ovarian activity. Cows were administered 0, 2.0, or 4.0 mg of TZD/kg of BW by intrajugular infusion once daily from 21 d before expected parturition until parturition. Plasma samples were collected daily from 22 d before expected parturition through 21 d postpartum and twice weekly from wk 4 through 9 postpartum. In response to increasing TZD dosage, plasma nonesterified fatty acid concentrations decreased linearly during the postpartum period (d 0 to +21: 348, 331, 268 +/- 31 microEq/L, respectively). Plasma concentrations of glucose were highest in cows administered 4.0 mg of TZD/kg of BW during the peripartum and postpartum periods (d -7 to +7: 57.9, 57.8, 61.1 +/- 0.8 mg/dL and d 0 to +21: 51.6, 49.3, 54.7 +/- 1.1 mg/dL, respectively). Plasma concentrations of beta-hydroxybutyrate were increased during the peripartum period by TZD administration (9.6, 9.9, 10.2 +/- 0.3 mg/dL) but were not affected during the postpartum period. Plasma insulin was not affected by treatment during any time period. Postpartum liver triglyceride content was decreased linearly (11.0, 10.4, 4.2 +/- 1.6%) and glycogen content was increased linearly (2.16, 2.38, 2.79 +/- 0.19%) by prepartum TZD administration. Prepartum TZD administration linearly increased DMI during the peripartum period (d -7 to +7: 16.1, 17.2, 17.3 +/- 0.5 kg/d). Cows administered TZD prepartum maintained higher postpartum body condition scores than control cows (wk 1 through 9: 2.77, 2.89, 3.02 +/- 0.05). There was no effect of prepartum TZD on milk yield; however, yields of 3.5% fat-corrected milk (52.2, 54.6, 48.0 +/- 1.6 kg/d) and most other milk components were decreased in cows that received 4.0 mg of TZD/kg of BW prepartum. Prepartum TZD administration linearly decreased the number of days to first ovulation (29.3, 28.3, 19.0 +/- 3.6 d). These results suggest that prepartum administration of TZD improves metabolic health and DMI of periparturient dairy cows and may decrease reliance on body fat reserves during early lactation.