Long-term molecular adaptations in liver from high-producing dairy cows are virtually unknown. Liver from five Holstein cows was biopsied at −65, −30, −14, +1, +14, +28, and +49 days relative to parturition for transcript profiling using a microarray consisting of 7,872 annotated cattle cDNA inserts. More than 5,000 cDNA elements represented on the microarray were expressed in liver. From this set we identified 62 differentially expressed genes related to physiological state, with a false discovery rate threshold of P = 0.20. The dominant expression pattern consisted of upregulation from day −30 through day +1, followed by downregulation through day +28. There was a threefold decrease from day −65 through day +14 in expression of IGFBP3, GSTM5, and PDPK1. These genes mediate IGF-I transport, oxidative stress, and glucose homeostasis, respectively. IGFBP3, EIF4B, and GSTM5 mRNA levels were positively correlated with blood serum total protein. Correlation analysis showed positive associations between serum nonesterified fatty acids and mRNA expression for SAA1, CPT1A, ACADVL, and TFAP2A. Transcript levels of ACSL1, PPARA, and TFAP2A were positively correlated with serum β-hydroxybutyrate. Expression patterns for certain genes (e.g., IGFBP3, HNF4A, GPAM) revealed adaptations commencing well ahead of parturition, suggesting they are regulated by factors other than periparturient hormonal environment. Results provide evidence that hepatic inflammatory responses occurring near parturition initiate or augment adipose catabolism. In this context, cytokines, acute-phase proteins, and serum nonesterified fatty acids are key players in periparturient cow metabolism. We propose a model for integrating gene expression, metabolite, and liver composition data to explain physiological events in placenta, adipose, and liver during the periparturient period.