Natural human interferon-alpha (nHuIFN alpha) was administered to actively training Standardbred racehorses with inflammatory airway disease (IAD). Inflammatory airway disease was characterized by poor exercise performance and inflammation and exudate in the upper and lower airway. Placebo, 50, 150, or 450 units(U) of nHuIFN alpha was administered orally for 5 consecutive days to eight horses per treatment group in a double-blind, randomized block design. Response to nHuIFN alpha was monitored by semiquantitative endoscopic examination score and cytologic examination of bronchoalveolar lavage fluid (BALF) performed at baseline (Day 1), Day 8 and Day 15 after initiation of nHuIFN alpha administration. Neutrophil, macrophage, lymphocyte, and nucleated cell counts in BALF were lower (P < 0.05), compared with BALF cell counts in placebo-treated horses 8 days after administration of 50 U and 150 U nHuIFN alpha, and 15 days after administration of 50 U nHuIFN alpha. Neutrophil, lymphocyte and nucleated cell counts were lower than cell counts from placebo-treated horses, 8 days following administration of 450 U nHuIFN alpha. The proportion CD4-, CD5-, and CD8-positive lymphocytes in BALF was not affected by administration of nHuIFN alpha. Oral administration of low-dose nHuIFN alpha reduced inflammation of the lowest respiratory tract in Standardbred racehorses with IAD.