Natural human interferon-alpha (nHuIFN-alpha) from three sources was given orally to 368 calves experiencing a natural outbreak of bovine respiratory disease complex (BRDC). In one study, 200 calves were given one treatment daily for 3 days of placebo or 20, 200, or 2,000 IU of nHuIFN-alpha before shipment. Calves treated with 20 or 200 IU had a significant (p < 0.05) weight gain benefit for the first 21 days in the feedlot, if they had rectal temperatures <40 degrees C when treated with nHuIFN-alpha. In a second trial, 168 mixed-breed calves (five groups randomized to 31-36 calves/group) were treated with one dose of placebo or 200 or 400 IU of nHuIFN-alpha after shipment to the feedlot. Using this regimen, a dose of 200 IU per calf significantly (p < 0.08) decreased the number of sick calves per group and delayed development of BRDC. Results of these studies demonstrate that oral administration of nHuIFN-alpha, which may partially mimic the nasally secreted IFN response reported during BRDC, may be beneficial in cattle.