The respiratory tract is the portal of entry and target organ of many aerosolized toxins and infective agents, and there is increasing need for testing the efficacy of potential therapeutic agents delivered directly into the lungs. Intratracheal instillation and aerosol inhalation are the two methods most often used to introduce drugs, toxins, or infective agents into the respiratory tract of experimental animals. In this study we compared the distribution and efficacy of antibodies given to mice by aerosol inhalation or intratracheal instillation. We determined the pulmonary distribution of these antibodies by immunohistochemistry and observed the distribution and severity of pulmonary lesions that developed after exposure to aerosolized ricin. Although antibodies administered by either method prevented death, we found that instilled antibodies tended to concentrate around terminal airways and often failed to reach peripheral lung fields. Sometimes entire lung lobes were missed by the instillation route. Acute and chronic pulmonary lesions developed in the unprotected areas of instillation-treated lungs. In contrast, aerosolized antibodies covered all pulmonary surfaces and effectively prevented ricin-induced lesions throughout the lungs. Our findings suggest that the aerosol inhalation method may be preferable for evaluating the efficacy of therapeutic agents in the respiratory tract because of the failure of instilled agents to reach and protect peripheral alveoli.