The aim of this work was to characterize lung function and cellular responses in a large animal model for chronic asthma. All sheep were sensitized to house dust mite (HDM) by subcutaneous injection of HDM before lung challenges. Groups of sheep were given weekly lung challenges with either HDM (n = 12) or saline (control, n = 5) for 3 months. Post challenge, there were significant increases in lung resistance in 7 out of 12 HDM-challenged sheep, compared to control sheep. In HDM-responding sheep, there was a progressive increase in the magnitude of HDM-induced resistance throughout the trial. All HDM-challenged sheep developed BAL eosinophilia and bronchial hyperresponsiveness. In conclusion, sheep chronically challenged intralung with HDM consistently develop airway hyperresponsiveness and eosinophilia, whereas allergen-specific bronchoconstriction is observed in just over half of these sheep.