The objective was to study the effects of body condition score (BCS) at calving on dairy performance, indicators of fat and protein mobilization, and metabolic and hormonal profiles during the periparturient period of Holstein-Friesian cows. Twenty-eight multiparous cows were classed according to their BCS (0 to 5 scale) before calving as low (BCS ≤2.5; n=9), medium (2.75≤BCS≤3.5; n=10), and high (BCS ≥3.75; n=9), corresponding to a mean of 2.33, 3.13, and 4.17 points of BCS, and preceding calving intervals of 362, 433, and 640d, respectively. Cows received the same diets based on preserved grass to allow ad libitum feed intake throughout the study, and lactation diet contained 30% of concentrate (dry-matter basis). Measurements and sampling were performed between wk −4 and 7 relative to calving. No significant effects were observed of BCS group on dry matter intake (kg/d), milk yield, BCS loss, plasma glucose, and insulin concentrations. The high-BCS group had the lowest postpartum energy balance and the greatest plasma concentrations of leptin prepartum, nonesterified fatty acids and β-hydroxybutyrate postpartum, insulin-like growth factor 1, and milk fat content. Milk fat yield was greater for the high- than the low-BCS group (1,681 vs. 1,417g/d). Low-BCS cows had the greatest concentration of medium-chain fatty acids (e.g., sum of 10:0 to 15:0, and 16:0), and the lowest concentration and secretion of preformed fatty acids (e.g., cis-9 18:1) in milk fat. Milk protein secretion was lowest in the low-BCS group, averaging 924, 1,051, and 1,009g/d for low-, medium-, and high-BCS groups, respectively. Plasma 3-methylhistidine was greater in wk 1 and 2 postpartum compared with other time points, indicating mobilization of muscle protein. Plasma creatinine tended to be lower and the 3-methylhistidine: creatinine ratio was greater in low- compared with medium- and high-BCS cows, suggesting less muscle mass but more intense mobilization of muscle protein in lean cows. High-BCS cows were metabolically challenged during early lactation due to intense mobilization of body fat. Conversely, limited availability of body fat in low-BCS cows was associated with increased plasma indicators of body protein mobilization during the first weeks of lactation, and lower milk protein secretion. These results should be confirmed using an experimental approach where calving BCS variation would be controlled by design.