Supplementation of dairy cows with trans-10, cis-12 conjugated linoleic acid (CLA) allows nutrient repartitioning despite an energy deficiency in early lactation, which might be a benefit for the immune system, too. In this study, we investigated potential nutrient sparing effects of CLA in early lactating cows with low plasma glucose concentrations exposed to an intramammary lipopolysaccharide (LPS) challenge. Fifteen multiparous Holstein cows were exposed to an intramammary LPS challenge in week 4 p.p. Eight cows (CLA) were supplemented daily with 70 g of lipid-encapsulated CLA (6.8 g trans-10, cis-12 and 6.6 g of the cis-9, trans-11 CLA isomer; CLA) and seven cows with 56 g of control fat (CON). Blood samples were obtained every 30 min along with rectal temperature, heart and respiratory rate, and milk samples were taken hourly until 10 hr after the LPS application. Plasma was analysed for concentrations of glucose, free fatty acids, beta-hydroxybutyrate (BHB), cortisol, insulin and glucagon. In milk, somatic cell count and activity of lactate dehydrogenase were determined. Initial plasma glucose concentration was lower in CLA than in CON. During the immunostimulation, CLA had higher glucose concentrations than CON, and BHB decreased distinctly in CLA, whereas CON cows maintained BHB concentration at a lower level. Body temperature in CLA increased earlier, the difference between peak and basal temperature was higher, and the decline thereafter occurred earlier. In conclusion, CLA supplementation of early lactating cows exposed to an intramammary LPS challenge affected local and systemic immune responses. We assume that CLA supplementation triggered glycogen storage. Cows supplemented with CLA provided more glucose and preferentially used BHB as an energy source during the immune response. The more intense metabolic and more concentrated endocrine responses support an immunomodulatory effect of CLA supplementation.