The objectives of this study were to determine the effects of oral supplementation with Saccharomyces cerevisiae fermentation products (SCFP; SmartCare and NutriTek; Diamond V, Cedar Rapids, IA) on immune function and bovine respiratory syncytial virus (BRSV) infection in preweaned dairy calves. Twenty-four Holstein x Angus, 1-2 day old calves (38.46 ± 0.91 kg initial body weight) were assigned two treatment groups: control; or SCFP treated, milk replacer with 1 g/d SCFP (SmartCare) and calf starter top-dressed with 5 g/d SCFP (NutriTek). The study consisted of one 31 d period. On d 19-21 of the supplementation period, calves were challenged via aerosol inoculation with BRSV strain 375. Calves were monitored twice daily for clinical signs, including rectal temperature, cough, nasal and ocular discharge, respiration effort and lung auscultation. Calves were euthanized on d 10 post infection (d 29-31 of the supplementation period) to evaluate gross lung pathology and pathogen load. Supplementation with SCFP did not affect body weight (P = 0.762) or average daily gain (P = 0.750), percentages of circulating white blood cells (P < 0.05), phagocytic (P = 0.427 for neutrophils and P = 0.460 for monocytes) or respiratory burst (P = 0.119 for neutrophils and P = 0.414 for monocytes) activity by circulating leukocytes either before or following BRSV infection, or serum cortisol concentrations (P = 0.321) after BRSV infection. Calves receiving SCFP had reduced clinical disease scores compared to control calves (P = 0.030); reduced airway neutrophil recruitment (P < 0.002); reduced lung pathology (P = 0.031); and a reduced incidence of secondary bacterial infection. Calves receiving SCFP shed reduced virus compared to control calves (P = 0.049) and tended towards lower viral loads in the lungs (P = 0.051). Immune cells from the peripheral blood of SCFP treated calves produced increased (P < 0.05) quantities of IL-6 and TNFα in response to toll-like receptor stimulation; while cells from the bronchoalveolar lavage (BAL) of SCFP treated calves secreted less (P < 0.05) proinflammatory cytokines in response to the same stimuli. Treatment with SCFP had no effect on virus-specific T cell responses in the blood, but resulted in reduced (P = 0.045) virus-specific IL-17 secretion by T cells in the BAL. Supplementing with SCFP modulates both systemic and mucosal immune responses and may improve the outcome of an acute respiratory viral infection in preweaned dairy calves.