Many apparently healthy cows show marked inflammatory conditions around calving, associated with endocrine and metabolic changes. To prevent the above conditions, a low-dose, oral interferon-alpha (IFN-alpha) treatment was carried out on periparturient, multiparous dairy cows. In the first trial, 10 cows received 10 IU of IFN-alpha/kg of BW daily during the last 2 wk of pregnancy. In a second trial, 4 cows received 0.5 IU of IFN-alpha/kg of BW daily until d 5 of lactation. In both trials, a homogenous group of untreated dairy cows was used as control. All cows were monitored, during the month before and after calving, for health status, BCS, milk yield, and inflammatory, metabolic, immune, and hematological variables. Compared with control cows, IFN-alpha-treated animals showed in both trials a larger decrease of BCS along with decreased milk yield (P < 0.05), increased haptoglobin (P < 0.05) and ceruloplasmin, and a slower increase of negative acute phase proteins (albumin, cholesterol, paraoxonase, vitamin A) after calving. Interferon-alpha-treated animals also showed a larger decrease of plasma glucose and greater values of NEFA, beta-hydroxybutyrate, and reactive oxygen metabolites. There also was evidence of IL-6 and tumor necrosis factor-alpha responses in both groups before calving with a quick decrease thereafter. The IL-6 response appeared in some animals regardless of the IFN-alpha treatment. Results indicate that low-dose IFN-alpha can sustain an inflammatory response in dairy cows and cause notable metabolic changes. This outcome might be explained by the repeated and extended interaction of IFN-alpha at low doses with the oral lymphoid tissues during rumination, as suggested by the observed stability of the cytokine in the rumen milieu; the final inflammatory effect could thus be as large as that of high doses. In addition, the antiflogistic signal of IFN-alpha might be counteracted and inverted by lymphocytes detected in the rumen liquor.