During early postpartum, high-producing dairy cows undergo a period of extensive tissue catabolism because of negative nutrient balance. Homeorrhetic controls assure that nutrients are partitioned to favor lactation at the same time that homeostasis secures survival. However, unrestrained metabolic disturbances often lead to diseases which, in turn, dramatically decrease both productive and reproductive performance. In early lactation, dairy cows are more susceptible to diseases, particularly those that affect the uterus, such as metritis, and the mammary gland, such as mastitis. It is thought that calving and the increase in nutrient demands with the onset of lactation affect the immune system causing a temporary dysregulation in immune function. Humoral and cellular immunity are usually depressed at the same time that inflammation is enhanced with parturition. Negative nutrient balance has been associated with compromised immune function in dairy cows, and low concentrations of glucose, insulin, and insulin-like growth factor (IGF)-1 associated with elevated concentrations of nonesterified fatty acids and ketone bodies can have disruptive and detrimental effects on immune cells. Reductions in blood concentrations of Ca and antioxidant vitamins that typically occur around parturition are also linked with impaired immune competence and increased risk of uterine diseases. Nevertheless, experimentally-induced negative nutrient balance alone have minor effects on the leukocyte function, does not seem to affect the clinical symptoms associated with an intramammary endotoxin infusion, and have minor effects on immunocompetence of cows challenged to develop mastitis. The disagreement between experimental models that use nutrient restriction to study negative nutrient balance and immunity and the observations of immunosuppression in periparturient dairy cows suggests that changes in immune function are complex; they likely involve nutritional imbalances associated with the physiological and endocrine state of the cow that leads to the dysregulation of the immune system and increased risk of diseases.