Instillation of crystalline silica into the lungs of mice is a common experimental model of pulmonary fibrosis. Typically, a suspension of silica in saline is injected into the trachea via intubation or surgical tracheostomy. These techniques require a high degree of technical skill, have a lengthy training period, and can suffer from a high failure rate. In oropharyngeal aspiration, a droplet of liquid is placed in the animal's mouth while simultaneously holding its tongue (to block the swallow reflex) and pinching its nose shut, forcing it to breathe through its mouth, aspirating the liquid. To determine whether oropharyngeal aspiration (OA) could replace intratracheal instillation (IT) in a model of silica-induced fibrosis, a comparison was performed. Crystalline silica was introduced into the lungs of male C57BL/6 mice by the IT or OA procedure, and the resulting inflammation and fibrosis was assessed after 3 weeks. IT and OA instillation of silica both resulted in neutrophilic inflammation and fibrotic changes, including interstitial fibrosis and dense fibrotic foci. Mice treated via IT demonstrated a few large lesions proximal to conducting airways with little involvement of the distal parenchyma and large interanimal variability. In contrast, OA resulted in a diffuse pathology with numerous fibrotic foci distributed throughout the lung parenchyma, which is more representative of human fibrotic lung disease. OA- but not IT-treated mice exhibited significantly increased lung collagen content. Furthermore, the interanimal variability within the OA group was significantly less than in the IT group. Oropharyngeal aspiration should be considered as an alternative to intratracheal instillation of silica and other particulates in studies of respiratory toxicity and lung disease.