During excessive body fat mobilization in early lactation, dairy cows experience a severe metabolic load. Here, a failure in metabolic adaptation often results in an increased susceptibility to health problems. In this study, we analyzed the genetic basis of the metabolic adaptability during the transition period. To this end, blood samples were taken from 178 cows (Holstein, Red Holstein, Fleckvieh and Braunvieh) at 3 critical stages: T1 = wk 3 before expected calving (not lactating and no metabolic load); T2 = wk 4 postpartum (lactating and high metabolic load), and T3 = wk 13 after parturition (lactating and no noteworthy metabolic load). Plasma concentrations of nonesterified fatty acids (NEFA), β-hydroxybutyrate (BHBA) and glucose, 3 metabolites characterizing the metabolic status and adaptability, were measured at T1, T2, and T3. All cows were genotyped with the Illumina next-generation High-Density Bovine BeadChip resulting in a data set of 777,692 SNPs. After quality control and filtering, the SNPs were annotated to known genes (Ensembl Genes Database) and pathways (KEGG Database). For each gene G with g SNPs, we performed a score test based on the linear regression model y = γ₁C₁ +…+ γ_mC_m + β₁S₁ +…+ β_gS_g + ε, where C_i are environmental or breed effects and y are either one of the 3 metabolites measured at T1, T2 or T3 or the ratio of their concentrations measured at the different points of time, to assess the association of the gene G to the phenotype y. The results were then used to identify pathways enriched with significant genes using a weighted Kolmogorov-Smirnov test. As a result, we found 99 significant genes associated with at least one of the 3 metabolites. For each metabolite, we found genes that are significant at T2 but not at T1 and T3 or vice versa. This strongly suggests the genes to be potential candidates for the adaptive regulation. We further find 3 pathways (steroid hormone biosynthesis, ether lipid metabolism and glycerophospholipid metabolism) to jointly affect the 3 metabolites. In conclusion, this may be regarded as evidence for the genetic basis for the adaptation performance of dairy cows and, at the same time, reveals its complexity.